跳到主要內容

臺灣博碩士論文加值系統

(100.28.2.72) 您好!臺灣時間:2024/06/13 13:39
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:吳芊瑩
研究生(外文):WU, CHIEN YING
論文名稱:探討HMGCS2基因表現與酮體對肝癌細胞sorafenib感受性之影響
論文名稱(外文):Study the effects of HMGCS2 expression and ketone body on sorafenib sensitivity in hepatocellular carcinoma cells
指導教授:廖宜真
指導教授(外文):LIAO, YI-JEN
口試委員:廖宜真涂玉青邱琬淳
口試委員(外文):LIAO, YI-JENTWU, YUH-CHINGCHIU, WAN-CHUN
口試日期:2023-06-15
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學檢驗暨生物技術學系碩士班
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:英文
論文頁數:77
中文關鍵詞:酮體肝細胞癌SorafenibRegorafenib
外文關鍵詞:Ketone bodyHepatocellular carcinomaSorafenibRegorafenib
相關次數:
  • 被引用被引用:0
  • 點閱點閱:34
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
肝細胞癌是全世界最常見的原發性惡性腫瘤。Sorafenib為multi-target kinase inhibitor並且有效抑制癌細胞增生與血管新生作用,是晚期肝細胞癌患者第一線口服抗癌藥物,然而長期使用sorafenib被證實產生抗藥性。近年來,許多研究指出糖解作用導致乳酸堆積促進抗藥性的生成,並且進一步影響肝細胞癌的治療效能。3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2)是酮體生成的限速酶,其協助合成酮體β-hydroxybutyrate (β-HB)與acetoacetate (AcAc)。β-HB是體內最多的酮體,其與AcAc以四比一的比例存在於人體中。近年來,酮體被證實會透過改變癌細胞代謝途徑與促進癌細胞凋亡的機轉協助癌症治療。我們先前的研究指出HMGCS2基因的表現被抑制會導致酮體的表現量下降,進而調控c-Myc/cyclin D1與caspase-dependent signaling促進肝細胞癌的進程。然而,HMGCS2調控之酮體生成是否會改變肝細胞癌對於sorafenib的感受性仍未知,並且給予酮體是否會對sorafenib抗藥性肝癌細胞代謝轉變產生影響仍未知。此研究中,我們發現當HMGCS2表現下降會透過活化磷酸化的ERK、p38與AKT相關路徑以降低sorafenib所誘導的抗細胞增生現象,相反地,過度表現HMGCS2會抑制ERK活化以提高sorafenib對於癌細胞的細胞毒殺效果。除此之外,我們發現在Huh7與HepG2細胞中同時給予sorafenib治療並抑制HMGCS2基因會透過降低ZO-1與提高c-Myc表現以促進癌細胞轉移能力。然而,在癌細胞過度表現HMGCS2基因並給予sorafenib治療並未改變轉移能力,也不降低ZO-1、c-Myc與N-cadherin的表現。最後,我們想確認HMGCS2的表現是否會藉由酮體依賴方式影響癌細胞對於sorafenib的感受性。我們發現β-HB預處理有效提高Huh7與HepG2中sorafenib所誘導的抗增生能力。此外,我們發現HMGCS2與酮體β-HB在四種不同的sorafenib抗藥性肝癌細胞中表現差異。低HMGCS2與β-HB表現的抗藥性肝癌細胞與高糖解作用與乳酸生成有相關。給予β-HB可以有效提高抗藥性肝癌細胞中PDH的表現,並且同時降低LDH與乳酸的堆積。除此之外,同時給予β-HB與sorafenib或regorafenib會透過抑制B-raf/MAPK與N-cadherin-vimentin路徑減緩抗藥性肝癌細胞的增生與轉移的能力。在小鼠實驗模型中,腹腔注射β-HB可以抑制抗藥性肝腫瘤增生蛋白與糖解作用蛋白的表現。本研究發現HMGCS2基因表現與酮體不但能減緩肝癌細胞增生與遠端轉移,還能透過降低無氧糖解作用與乳酸堆積逆轉抗藥性,並且協同第一線與第二線抗癌藥物治療肝癌。
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide. Sorafenib, which is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis, is a first-line drug for advanced-stage HCC patient, however, long-term treatment often results in acquired resistance. Recently, glycolysis-mediated lactate production was reported to contribute to drug resistance and disturb the HCC treatment efficacy. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, β-hydroxybutyrate (β-HB) and acetoacetate (AcAc). β-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment has been shown to have therapeutic effects against many cancers by inducing metabolic alterations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, it remains unclear whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment and whether ketone body treatment alters the metabolic shift in sorafenib-resistant HCC cells. Herein, we showed that HMGCS2 downregulation attenuated the anti-proliferative effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-p38, and p-AKT. In contrast, HMGCS2 overexpression enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown of HMGCS2 promoted migratory ability by inhibiting zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin were decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether HMGCS2 expression influenced sorafenib sensitivity in a ketone-dependent manner. We showed that β-HB pretreatment significantly enhanced the anti-proliferative effects of sorafenib in both Huh7 and HepG2 cells. Furthermore, we found differential expressions of HMGCS2 and the ketone body, β-HB, in four different sorafenib-resistant HCC cell lines. Lower levels of HMGCS2 and β-HB correlated with higher glycolytic alterations and lactate production in sorafenib-resistant HCC cells. β-HB treatment enhanced the expression of pyruvate dehydrogenase (PDH) and decreased lactate dehydrogenase (LDH) and lactate production in sorafenib-resistant HCC cells. Additionally, β-HB combined with sorafenib or regorafenib promoted the anti-proliferative and anti-migratory abilities of sorafenib-resistant HCC cells by inhibiting the B-raf/mitogen-activated protein kinase (MAPK) pathway and mesenchymal N-cadherin-vimentin axis. In vivo β-HB administration ameliorated subcutaneous sorafenib-resistant tumors by inhibiting expressions of proliferative and glycolytic proteins. Collectively, this study supported the positive therapeutic effect of HMGCS2 and β-HB through limiting cell proliferation and migration in both parental and sorafenib-resistant HCC cells, moreover, and may serve as another energy source that downregulated lactate production and reversed sorafenib resistance by inducing a glycolytic shift, which was also found to possess a synergetic ability with second-line drug treatment in sorafenib-resistant HCC cells.
Table of contents
Chinese abstract.……………………………………………………………………….……………………….……P. 6
English abstract……………………………………………………………………………………………….………P. 8
I. Introduction
A. Progression of liver cancer….…..……………………………………..………….……P. 10
B. Treatment of liver cancer……………………………………………………….…………P. 11
C. Drug resistance of liver cancer…..……………………….……………………………P. 13
D. Ketone body metabolism…..………………………………………………….………….P. 15
E. Applications of ketone body in disease treatments……………………………P. 17
F. Applications of ketone body in cancers therapies………………………..…...P. 18
II. Objective……………………………………………………………………………………………….………P. 21
III. Material and methods
A. Study Flow Chart………………………………………………………………………………..…P. 22
B. Cell Culture and Viral Infection…………………………………………………………..…P. 22
C. Generation of Sorafenib-Resistant (SR) Cells……………………………………..…P. 23
D. Cell Viability Assay………………………………………………………………….……….…..P. 23
E. Western Blot Analysis……………………………………………………………………………P. 23
F. Wound-Healing Migration Assay……………………………………......................…P. 25
G. β-HB Quantification…………………………………………………………………………...…P. 25
H. AcAc Quantification………………………………...............................................…P. 25
I. Lactate Quantification………………………………............................................…P. 25
J. Free Fatty Acid Quantification………………………………...............................…P. 26
K. RNA Extraction and Reverse Transcription (RT)-Quantitative Polymerase Chain Reaction (qPCR)…………………………................................................…P. 26
L. Immunohistochemistry Staining (IHC)…………………………........................…P. 27
M. Gene expression and Ingenuity Pathway Analysis (IPA) …………………....…P. 27
N. Apoptosis assay…………………………………………………………….…………………....…P. 28
O. Animal Experiment…………………………………………………………………………....…P. 28
P. Statistical Analyses…………………………………………………………………….…….……P. 28
IV. Results
A. The sorafenib-induced anti-proliferative effect was influenced via the Akt/MAPK axis in the gain or loss of HMGCS2 function in the HCC cells…………….……...……………………………………….……………………………………..…P. 30
B. HMGCS2 loss reversed sorafenib-induced migratory inhibition while expressed no significant effect in HMGCS2-overexpressing cells…………………………………………………………………………………………….………...P. 31
C. Pretreatment with a ketone body (β-HB) enhanced the cytotoxic effect of sorafenib in parental HCC cells…………………………………….……………………..…P. 31
D. Differential levels of HMGCS2 and β-HB rather than AcAc regulated glucose metabolism instead of fatty acid metabolism in the four sorafenib-resistant HCC cell lines………………………………………………………………………………..………P. 32
E. β-HB treatment reverses the glycolysis-related sorafenib resistance in Huh7 and Sk-Hep-1 cells…………………………………………………………….…………..………P. 35
F. β-HB treatment reverses sorafenib resistance and enhances the regorafenib sensitivity through improving the anti-proliferative and anti-migratory effects in sorafenib-resistant HCC cells……..…………………………………………………..…P. 36
G. β-HB treatment decreased proliferation and metabolic proteins expression in sorafenib-resistant HCC tumors……………………………………………………….…….P. 38
V. Discussions
A. Autophagy in sorafenib-resistant HCC………………………………..….……..........P. 39
B. Roles of HMGCS2 expression in cancer progression………………….…….....…P. 39
C. Application of ketone bodies treatment in cancers……………..……………………P. 41
D. Ketosis and ketoacidosis in human………………………………………………………….P. 43
E. Evaluating the application of ketone bodies in HCC treatment…………..……P. 44
VI. Conclusions………………………………………………………………………………………….……….P. 45
VII. References……………………………………………………………………..………….………………….P. 47
VIII. Appendix……………………………………………………………………….……………………………..P. 74
A. HMGCS2-Mediated Ketone Level Affect Sorafenib Treatment Efficacy in Liver
B. 2022 Teacher and Student Joint Academic Research Symposium Certification of Attendance and Presentation
C. Asian Pacific Association for the Study of liver (APASL) 2023 Certification of Attendance
D. 2023 Teacher and Student Joint Academic Research Symposium Certification of Attendance and Presentation

List of Figures and Tables
I. Figure 1. Knockdown of the HMGCS2 gene increased cell proliferation and decreased sorafenib sensitivity through promoting the mitogen-activated protein kinase (MAPK) and Akt signaling pathway in Huh7 and HepG2 cells……….……………………………………………………………………………………….………..P. 58
II. Figure 2. Overexpression of HMGCS2 in sorafenib-treated Huh7 and HepG2 cells exhibited an inhibitory effect on mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) activation……….……..P. 59
III. Figure 3. HMGCS2-knockdown enhanced the migratory ability and epithelial-mesenchymal transition of sorafenib-treated Huh7 and HepG2 cells……..….P. 60
IV. Figure 4. HMGCS2 overexpression did not affect the migratory ability but decreased expressions of N-cadherin and c-Myc in both sorafenib-treated Huh7 and HepG2 cells……….……………………………………………………………………………….P. 61
V. Figure 5. β-Hydroxybutyrate (β-HB) pretreatment decreased cell proliferative ability and enhanced the sorafenib sensitivity in hepatocellular carcinoma (HCC) cells……….……………………………………………………………………….……….……P. 63
VI. Figure 6. Different level of HMGCS2 influenced β-HB rather than AcAc in four HCC-SR cell lines; moreover, fatty acid-mediated pathways were not related to β-HB levels in the four SR cell lines……….…………………………..…….P. 64
VII. Figure 7. Ingenuity Pathway Analysis (IPA) analyses of upregulated pathways in sorafenib-resistant Huh7 cells……….………………..…………………….P. 65
VIII. Figure 8. Differential expressions of PDH, LDHA, and lactate in four different sorafenib-resistant HCC cells……….………………………..…………….…….P. 66
IX. Figure 9. β-HB treatment altered expression levels of PDH, LDHA, and lactate in Huh7-SR and Sk-Hep-1-SR cells………………………………………………….………P. 67
X. Figure 10. β-HB treatment reversed sorafenib resistance and enhanced regorafenib sensitivity through inhibiting the B-raf/MAPK pathway in Huh7-SR and Sk-Hep-1-SR cells……….………………………………………………………….……P. 68
XI. Figure 11. β-HB cotreatment enhanced the anti-migratory effect of regorafenib through suppressing the N-cadherin/vimentin axis in Huh7-SR and Sk-Hep-1-SR cells……….………………………………………………………………………………..………….P. 70
XII. Figure 12. β-HB administration caused decreased PCNA and LDHA expressions, but increased PDH in tumor-bearing xenograft mice…..…….….P. 71
XIII. Figure 13. Proposed model demonstrating the mechanisms of HMGCS2 downregulation mediating ketone reduction in disturbing clinical treatment in parental and sorafenib-resistant hepatocellular carcinoma (HCC) cells…..…P. 72
XIV. Table 1. Sequence primers……………………………………………….……………….……P. 73

1.Siegel, R.L., et al., Cancer statistics, 2023. CA Cancer J Clin, 2023. 73(1): p. 17-48.
2.Torimura, T. and H. Iwamoto, Treatment and the prognosis of hepatocellular carcinoma in Asia. Liver Int, 2022. 42(9): p. 2042-2054.
3.Zhang, C.H., et al., Changing epidemiology of hepatocellular carcinoma in Asia. Liver Int, 2022. 42(9): p. 2029-2041.
4.國家衛生研究院. 2月4日世界癌症日. 2023; Available from: https://enews.nhri.edu.tw/health/8945/.
5.Ogunwobi, O.O., et al., Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol, 2019. 25(19): p. 2279-2293.
6.Wu, B., Q.H. Sodji, and A.K. Oyelere, Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges. Cancers (Basel), 2022. 14(3).
7.Tsoris, A. and C.A. Marlar, Use Of The Child Pugh Score In Liver Disease, in StatPearls. 2022: Treasure Island (FL).
8.Cha, C. and R.P. Dematteo, Molecular mechanisms in hepatocellular carcinoma development. Best Pract Res Clin Gastroenterol, 2005. 19(1): p. 25-37.
9.Berumen, J., et al., Liver fibrosis: Pathophysiology and clinical implications. WIREs Mech Dis, 2021. 13(1): p. e1499.
10.Caligiuri, A., et al., Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells, 2021. 10(10).
11.Sarveazad, A., et al., Predictors of 5 year survival rate in hepatocellular carcinoma patients. J Res Med Sci, 2019. 24: p. 86.
12.Ahn, J.C., et al., Detection of circulating tumor cells and their implications as a biomarker for diagnosis, prognostication, and therapeutic monitoring in hepatocellular carcinoma. Hepatology, 2021. 73(1): p. 422-436.
13.Ayoub, W.S., et al., Current status of hepatocellular carcinoma detection: screening strategies and novel biomarkers. Ther Adv Med Oncol, 2019. 11: p. 1758835919869120.
14.Rimassa, L., T. Pressiani, and P. Merle, Systemic Treatment Options in Hepatocellular Carcinoma. Liver Cancer, 2019. 8(6): p. 427-446.
15.Temraz, S., et al., Liquid biopsy derived circulating tumor cells and circulating tumor DNA as novel biomarkers in hepatocellular carcinoma. Expert Rev Mol Diagn, 2022. 22(5): p. 507-518.
16.Yang, J.C., et al., Clinical Applications of Liquid Biopsy in Hepatocellular Carcinoma. Front Oncol, 2022. 12: p. 781820.
17.Sidali, S., et al., New concepts in the treatment of hepatocellular carcinoma. United European Gastroenterol J, 2022. 10(7): p. 765-774.
18.Awosika, J. and D. Sohal, A narrative review of systemic treatment options for hepatocellular carcinoma: state of the art review. J Gastrointest Oncol, 2022. 13(1): p. 426-437.
19.Yang, J.D., et al., A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 2019. 16(10): p. 589-604.
20.Zhu, Y.J., et al., New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin, 2017. 38(5): p. 614-622.
21.Kudo, M., et al., Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet, 2018. 391(10126): p. 1163-1173.
22.Zhang, H., et al., Recent advances in systemic therapy for hepatocellular carcinoma. Biomark Res, 2022. 10(1): p. 3.
23.Sas, Z., et al., Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J Mol Sci, 2022. 23(7).
24.Xiang, Q., et al., Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET. Clin Cancer Res, 2014. 20(11): p. 2959-70.
25.Gauthier, A. and M. Ho, Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res, 2013. 43(2): p. 147-54.
26.Wei, L., et al., The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma. Mol Cancer, 2019. 18(1): p. 147.
27.Niu, L., et al., New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 2017. 1868(2): p. 564-570.
28.Tang, W., et al., The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther, 2020. 5(1): p. 87.
29.Fornari, F., et al., Elucidating the Molecular Basis of Sorafenib Resistance in HCC: Current Findings and Future Directions. J Hepatocell Carcinoma, 2021. 8: p. 741-757.
30.Galun, D., et al., Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies. J Hepatocell Carcinoma, 2017. 4: p. 93-103.
31.Gao, R., et al., USP29-mediated HIF1alpha stabilization is associated with Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis. Oncogenesis, 2021. 10(7): p. 52.
32.Chen, J., et al., Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Lett, 2015. 367(1): p. 1-11.
33.Zhao, H., et al., Stabilization of snail maintains the sorafenib resistance of hepatocellular carcinoma cells. Arch Biochem Biophys, 2021. 699: p. 108754.
34.He, C., et al., MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget, 2015. 6(30): p. 28867-81.
35.Yang, F., et al., MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technol Cancer Res Treat, 2014. 13(1): p. 77-86.
36.Mu, W., et al., miR-27b synergizes with anticancer drugs via p53 activation and CYP1B1 suppression. Cell Res, 2015. 25(4): p. 477-95.
37.Marin, J.J.G., et al., Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers (Basel), 2020. 12(6).
38.Kaelin, W.G., Jr. and C.B. Thompson, Q&A: Cancer: clues from cell metabolism. Nature, 2010. 465(7298): p. 562-4.
39.Nava, G.M. and L.A. Madrigal Perez, Metabolic profile of the Warburg effect as a tool for molecular prognosis and diagnosis of cancer. Expert Rev Mol Diagn, 2022. 22(4): p. 439-447.
40.McNally, M.A. and A.L. Hartman, Ketone bodies in epilepsy. J Neurochem, 2012. 121(1): p. 28-35.
41.Ulamek-Koziol, M., et al., Ketogenic Diet and Epilepsy. Nutrients, 2019. 11(10).
42.Grabacka, M., et al., Regulation of Ketone Body Metabolism and the Role of PPARalpha. Int J Mol Sci, 2016. 17(12).
43.Puchalska, P. and P.A. Crawford, Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metab, 2017. 25(2): p. 262-284.
44.Vallejo, F.A., et al., The contribution of ketone bodies to glycolytic inhibition for the treatment of adult and pediatric glioblastoma. J Neurooncol, 2020. 147(2): p. 317-326.
45.Yellen, G., Ketone bodies, glycolysis, and KATP channels in the mechanism of the ketogenic diet. Epilepsia, 2008. 49 Suppl 8: p. 80-2.
46.Zhang, S. and C. Xie, The role of OXCT1 in the pathogenesis of cancer as a rate-limiting enzyme of ketone body metabolism. Life Sci, 2017. 183: p. 110-115.
47.Hwang, C.Y., et al., Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer. Nutrients, 2022. 14(22).
48.Watanabe, S., et al., Basic ketone engine and booster glucose engine for energy production. Diabetes Res Open J, 2016. 2(1): p. 14-23.
49.Shafqat, N., et al., Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. J Mol Biol, 2010. 398(4): p. 497-506.
50.Wang, Y.H., et al., HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma. Cancers (Basel), 2019. 11(12).
51.Puchalska, P. and P.A. Crawford, Metabolic and Signaling Roles of Ketone Bodies in Health and Disease. Annu Rev Nutr, 2021. 41: p. 49-77.
52.Porter, W.H., H.H. Yao, and D.G. Karounos, Laboratory and clinical evaluation of assays for beta-hydroxybutyrate. Am J Clin Pathol, 1997. 107(3): p. 353-8.
53.Cantrell, C.B. and S.S. Mohiuddin, Biochemistry, ketone metabolism. 2020.
54.Zhang, J., et al., Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo. J Lipid Res, 2018. 59(4): p. 625-634.
55.Huang, D., et al., Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress. Cell Res, 2016. 26(10): p. 1112-1130.
56.Feng, S., et al., Multi-dimensional roles of ketone bodies in cancer biology: Opportunities for cancer therapy. Pharmacol Res, 2019. 150: p. 104500.
57.Rojas-Morales, P., E. Tapia, and J. Pedraza-Chaverri, beta-Hydroxybutyrate: A signaling metabolite in starvation response? Cell Signal, 2016. 28(8): p. 917-23.
58.Møller, N., Ketone body, 3-hydroxybutyrate: minor metabolite-major medical manifestations. The Journal of Clinical Endocrinology & Metabolism, 2020. 105(9): p. 2884-2892.
59.Mizuno, Y., et al., The diabetic heart utilizes ketone bodies as an energy source. Metabolism, 2017. 77: p. 65-72.
60.Song, J.P., et al., Elevated plasma beta-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy. Sci Transl Med, 2020. 12(530).
61.Yurista, S.R., et al., Ketone bodies for the failing heart: fuels that can fix the engine? Trends Endocrinol Metab, 2021. 32(10): p. 814-826.
62.Hashim, S.A. and T.B. VanItallie, Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. J Lipid Res, 2014. 55(9): p. 1818-26.
63.Youm, Y.H., et al., The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med, 2015. 21(3): p. 263-9.
64.Koutnik, A.P., D.P. D'Agostino, and B. Egan, Anticatabolic Effects of Ketone Bodies in Skeletal Muscle. Trends Endocrinol Metab, 2019. 30(4): p. 227-229.
65.Kolb, H., et al., Ketone bodies: from enemy to friend and guardian angel. BMC Med, 2021. 19(1): p. 313.
66.Jensen, N.J., et al., Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases. Int J Mol Sci, 2020. 21(22).
67.Tomita, I., et al., SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition. Cell Metab, 2020. 32(3): p. 404-419 e6.
68.Dabek, A., et al., Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States. Nutrients, 2020. 12(3).
69.Ruan, H.B. and P.A. Crawford, Ketone bodies as epigenetic modifiers. Curr Opin Clin Nutr Metab Care, 2018. 21(4): p. 260-266.
70.Weber, D.D., et al., Ketogenic diet in the treatment of cancer - Where do we stand? Mol Metab, 2020. 33: p. 102-121.
71.Sainero-Alcolado, L., et al., Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ, 2022. 29(7): p. 1304-1317.
72.Wan, S., et al., HMGCS2 functions as a tumor suppressor and has a prognostic impact in prostate cancer. Pathol Res Pract, 2019. 215(8): p. 152464.
73.Zou, K., et al., Potential Role of HMGCS2 in Tumor Angiogenesis in Colorectal Cancer and Its Potential Use as a Diagnostic Marker. Can J Gastroenterol Hepatol, 2019. 2019: p. 8348967.
74.Ding, R., et al., HMGCS2 in metabolic pathways was associated with overall survival in hepatocellular carcinoma: A LASSO-derived study. Sci Prog, 2021. 104(3): p. 368504211031749.
75.Han, P., et al., Epigenetic inactivation of hydroxymethylglutaryl CoA synthase reduces ketogenesis and facilitates tumor cell motility in clear cell renal carcinoma. Pathol Res Pract, 2021. 227: p. 153622.
76.Suk, F.M., et al., HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells. Molecules, 2022. 27(22).
77.Shukla, S.K., et al., Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab, 2014. 2: p. 18.
78.Allen, B.G., et al., Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clin Cancer Res, 2013. 19(14): p. 3905-13.
79.Otto, C., et al., Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer, 2008. 8: p. 122.
80.Nencioni, A., et al., Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer, 2018. 18(11): p. 707-719.
81.Plotti, F., et al., Diet and Chemotherapy: The Effects of Fasting and Ketogenic Diet on Cancer Treatment. Chemotherapy, 2020. 65(3-4): p. 77-84.
82.Cui, W., et al., Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients. Front Oncol, 2019. 9: p. 1422.
83.Dmitrieva-Posocco, O., et al., beta-Hydroxybutyrate suppresses colorectal cancer. Nature, 2022. 605(7908): p. 160-165.
84.Vasan, N., J. Baselga, and D.M. Hyman, A view on drug resistance in cancer. Nature, 2019. 575(7782): p. 299-309.
85.Ward, R.A., et al., Challenges and Opportunities in Cancer Drug Resistance. Chem Rev, 2021. 121(6): p. 3297-3351.
86.Mikami, D., et al., beta-Hydroxybutyrate enhances the cytotoxic effect of cisplatin via the inhibition of HDAC/survivin axis in human hepatocellular carcinoma cells. J Pharmacol Sci, 2020. 142(1): p. 1-8.
87.Wang, Y.H., F.M. Suk, and Y.J. Liao, Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer. Cancers (Basel), 2020. 12(7).
88.Ha, T.Y., et al., Sorafenib inhibits migration and invasion of hepatocellular carcinoma cells through suppression of matrix metalloproteinase expression. Anticancer Res, 2015. 35(4): p. 1967-76.
89.Torii, S., et al., ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci, 2006. 97(8): p. 697-702.
90.Balasse, E.O. and F. Fery, Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev, 1989. 5(3): p. 247-70.
91.McGarry, J.D. and D.W. Foster, Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem, 1980. 49: p. 395-420.
92.Deblon, N., et al., Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. PLoS One, 2011. 6(9): p. e25565.
93.Nakagawa, H., et al., Lipid Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers (Basel), 2018. 10(11).
94.Zuo, J., et al., Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis. Front Immunol, 2021. 12: p. 779787.
95.Xu, S. and H.R. Herschman, A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers. Cancer Res, 2019. 79(23): p. 5907-5914.
96.Saed, C.T., S.A. Tabatabaei Dakhili, and J.R. Ussher, Pyruvate Dehydrogenase as a Therapeutic Target for Nonalcoholic Fatty Liver Disease. ACS Pharmacol Transl Sci, 2021. 4(2): p. 582-588.
97.Ishida, T., et al., Metabolic remodeling during somatic cell reprogramming to induced pluripotent stem cells: involvement of hypoxia-inducible factor 1. Inflamm Regen, 2020. 40: p. 8.
98.Marcucci, F. and C. Rumio, Glycolysis-induced drug resistance in tumors-A response to danger signals? Neoplasia, 2021. 23(2): p. 234-245.
99.Peng, J., et al., Altered glycolysis results in drug-resistant in clinical tumor therapy. Oncol Lett, 2021. 21(5): p. 369.
100.Alhourani, A.H., et al., Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells. Sci Rep, 2021. 11(1): p. 10487.
101.Gao, L., et al., Nrf2 signaling promotes cancer stemness, migration, and expression of ABC transporter genes in sorafenib-resistant hepatocellular carcinoma cells. PLoS One, 2021. 16(9): p. e0256755.
102.Fouquet, G., et al., Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition. Cancers (Basel), 2022. 14(4).
103.Kelekar, A., Autophagy. Annals of the New York Academy of Sciences, 2006. 1066(1): p. 259-271.
104.Sun, T., H. Liu, and L. Ming, Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma. Cell Physiol Biochem, 2017. 44(2): p. 716-727.
105.Wong, M.M., et al., Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Mol Biol Rep, 2021. 48(4): p. 3695-3717.
106.Mascaro, C., et al., Molecular cloning and tissue expression of human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. Arch Biochem Biophys, 1995. 317(2): p. 385-90.
107.Wang, J., et al., Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer. Int J Cancer, 2017. 140(11): p. 2484-2497.
108.Saraon, P., et al., Quantitative proteomics reveals that enzymes of the ketogenic pathway are associated with prostate cancer progression. Molecular & Cellular Proteomics, 2013. 12(6): p. 1589-1601.
109.Camarero, N., et al., Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer. Mol Cancer Res, 2006. 4(9): p. 645-53.
110.Lee, Y.E., et al., The prognostic impact of lipid biosynthesis-associated markers, HSD17B2 and HMGCS2, in rectal cancer treated with neoadjuvant concurrent chemoradiotherapy. Tumour Biol, 2015. 36(10): p. 7675-83.
111.Su, S.G., et al., miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma. Int J Biochem Cell Biol, 2017. 91(Pt A): p. 53-59.
112.Martinez-Outschoorn, U.E., et al., Ketone body utilization drives tumor growth and metastasis. Cell Cycle, 2012. 11(21): p. 3964-71.
113.Chen, S.W., et al., HMGCS2 enhances invasion and metastasis via direct interaction with PPARalpha to activate Src signaling in colorectal cancer and oral cancer. Oncotarget, 2017. 8(14): p. 22460-22476.
114.Bai, M., et al., LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease. EMBO Mol Med, 2023. 15(2): p. e16581.
115.Gui, T., et al., The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-beta-Induced Epithelial-Mesenchymal Transition. J Signal Transduct, 2012. 2012: p. 289243.
116.Yousefnia, S., et al., Mechanistic pathways of malignancy in breast cancer stem cells. Frontiers in Oncology, 2020. 10: p. 452.
117.Guo, H., et al., TGF-β1-induced EMT activation via both Smad-dependent and MAPK signaling pathways in Cu-induced pulmonary fibrosis. Toxicology and Applied Pharmacology, 2021. 418: p. 115500.
118.Hamidi, A.A., et al., Long non-coding RNAs as the critical regulators of epithelial mesenchymal transition in colorectal tumor cells: an overview. Cancer Cell International, 2022. 22(1): p. 1-15.
119.Wan, S., et al., HMGCS2 functions as a tumor suppressor and has a prognostic impact in prostate cancer. Pathology-Research and Practice, 2019. 215(8): p. 152464.
120.Weis, E.M., et al., Ketone body oxidation increases cardiac endothelial cell proliferation. EMBO Mol Med, 2022. 14(4): p. e14753.
121.Liao, Y.J., et al., Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl4 and TAA-Induced Liver Fibrosis in Mice. Int J Mol Sci, 2021. 22(6).
122.O'Neill, B. and P. Raggi, The ketogenic diet: Pros and cons. Atherosclerosis, 2020. 292: p. 119-126.
123.Stubbs, B.J., et al., A Ketone Ester Drink Lowers Human Ghrelin and Appetite. Obesity (Silver Spring), 2018. 26(2): p. 269-273.
124.Wiers, C.E., et al., Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents. Sci Adv, 2021. 7(15).
125.Poff, A.M., A.P. Koutnik, and B. Egan, Nutritional Ketosis with Ketogenic Diets or Exogenous Ketones: Features, Convergence, and Divergence. Curr Sports Med Rep, 2020. 19(7): p. 251-259.
126.Poff, A.M., et al., Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. Int J Cancer, 2014. 135(7): p. 1711-20.
127.Chen, J., et al., Identification of beta-hydroxybutyrate as a potential biomarker for female papillary thyroid cancer. Bioanalysis, 2019. 11(6): p. 461-470.
128.Huang, C.K., et al., Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via beta-hydroxybutyrate. Nat Commun, 2017. 8: p. 14706.
129.Rodrigues, L.M., et al., The action of beta-hydroxybutyrate on the growth, metabolism and global histone H3 acetylation of spontaneous mouse mammary tumours: evidence of a beta-hydroxybutyrate paradox. Cancer Metab, 2017. 5: p. 4.
130.Kadochi, Y., et al., Remodeling of energy metabolism by a ketone body and medium-chain fatty acid suppressed the proliferation of CT26 mouse colon cancer cells. Oncol Lett, 2017. 14(1): p. 673-680.
131.Grabacka, M.M., et al., Fenofibrate Induces Ketone Body Production in Melanoma and Glioblastoma Cells. Front Endocrinol (Lausanne), 2016. 7: p. 5.
132.Gouirand, V., et al., Ketogenic HMG-CoA lyase and its product beta-hydroxybutyrate promote pancreatic cancer progression. EMBO J, 2022. 41(9): p. e110466.
133.Sperry, J., et al., Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy. iScience, 2020. 23(9): p. 101453.
134.Abushawish, K.Y.I., et al., Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines. Int J Mol Sci, 2022. 23(19).
135.Feng, J., et al., Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1alpha/PPAR-gamma/PKM2-mediated glycolysis. J Exp Clin Cancer Res, 2020. 39(1): p. 24.
136.Feng, J., et al., Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res, 2020. 39(1): p. 126.
137.Gnocchi, D., et al., Inhibition of LPAR6 overcomes sorafenib resistance by switching glycolysis into oxidative phosphorylation in hepatocellular carcinoma. Biochimie, 2022. 202: p. 180-189.
138.Blanco, J.C., et al., Starvation ketoacidosis due to the ketogenic diet and prolonged fasting–a possibly dangerous diet trend. The American journal of case reports, 2019. 20: p. 1728.
139.Allen, B.G., et al., Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol, 2014. 2: p. 963-70.
140.Kolwicz, S.C., Jr., Ketone Body Metabolism in the Ischemic Heart. Front Cardiovasc Med, 2021. 8: p. 789458.
141.Yao, A., et al., On the nutritional and therapeutic effects of ketone body D-beta-hydroxybutyrate. Appl Microbiol Biotechnol, 2021. 105(16-17): p. 6229-6243.


電子全文 電子全文(網際網路公開日期:20250701)
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊