臺灣博碩士論文加值系統

由於Tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) 此蛋白對腫瘤細胞有高度的選擇性，因此被認為是個極有潛力的抗癌療法物質。TRAIL具有四個主要的接受器：DR4、DR5、DcR1、以及DcR2，前兩者的活化可以招集FADD以傳遞死亡訊息，然而後兩者則與TRAIL結合以中和TRAIL產生的毒性。熱休克蛋白HSP90對於許多真核生物蛋白質激脢及核內荷爾蒙接收器的活化是必須的，可幫助其目標蛋白的正確折疊，在細胞訊號傳遞及癌症發展過程扮演重要的角色。HSP90抑制劑對腫瘤細胞內的HSP90較正常細胞有100倍以上的親和力，可誘導腫瘤細胞生長停止進而引發細胞凋亡。在本篇研究中，我們發現在大腸腫瘤細胞中，HSP90抑制劑可以促進腫瘤細胞的DR5表現量上升(DR4, DcR1以及DcR2則不受影響)進而增強TRAIL對腫瘤細胞的毒殺性。一般常見調控DR5基因的分子機轉不外乎是經由p53、CHOP、或是NF-kB的調節，然而在我們的實驗中，我們發現HSP90抑制劑使DR5表現量上升是經由「後轉錄」的機制，且更發現了熱休克蛋白HSP70可以經由HSP90抑制劑的促進，進而接上DR5以增強其蛋白質結構穩定性。「低氧環境」被認為是固體腫瘤生長條件的重要特徵之一，其可促使腫瘤細胞對化學療法的耐受性。在本篇研究中，我們發現當腫瘤細胞處於低氧環境中，其細胞表面的DcR2誘餌受體的表現量會上升，但DR4, DR5及DcR1則不受影響。此外，我們發現HIF-1alpha對DcR2的基因調節扮演重要的角色。我們認為TRAIL是個相當有希望的抗癌療法，若能更深度了解TRAIL接受器的調控，將可以更有效的促進TRAIL對腫瘤細胞的毒殺性。在本篇研究中，我們發現DR5的表現量會受到HSP90抑制劑的促進，同時，其現象是經由HSP70增進DR5的穩定性所致。此外，固體腫瘤細胞於低氧環境，活化了HIF-1

Tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) is a promising candidate in anti-tumor therapy because of its high selectivity towards cancer cells. TRAIL has four major distinct receptors: DR4 and DR5 can recruit FADD to induce extrinsic death signal; DcR1 and DcR2 are decoy receptors, which can neutralize TRAIL toxicity by binding to TRAIL. In this study we investigated the effects of HSP90 inhibitors and hypoxia on TRAIL receptors expression in five different human colon cancer cell lines (HCT-116, HT-29, SW-480, SW-620, and WiDr). We found that several HSP90 inhibitors can synergistically enhance TRAIL toxicity in colon cancer cells accompanying by the upregulation of DR5 protein expression. DR4, DcR1 and DcR2 expression were not changed by HSP90 inhibitors. The DR5 upregulation is associated with post-translational mechanism, but unrelated to the gene transcription resulting from the activity of p53, CHOP and NF-kB, which are three major transcription factors identified for DR5 gene expression. Our results revealed that HSP70 upregulation following HSP90 inhibition can associate with DR5 and contribute to DR5 protein stabilization. We also found that hypoxia, an important feature of solid tumors and rendering tumor cells resistant to some chemotherapeutic reagents, is able to upregulate DcR2 protein expression in colon cancer cells. However hypoxia does not affect DR4, DR5 and DcR1 protein levels. RT-PCR study suggests this protein increase is resulting from DcR2 gene transcription. Exploring transcription factor(s) by using p53-null cells, pharmacological inhibitors as well as siRNA approach, our results revealed that hypoxia-dependent HIF-1α activation plays a crucial role in the gene transcription of DcR2, while neither p53 nor NF-kB has contribution in this action.
In conclusion, given that TRAIL-mediated tumor cell apoptosis is a promising antitumor strategy, conditions or factors which modulate TRAIL receptors might affect tumor sensitivity to TRAIL. In this study, we found that DR5 protein is stabilized by HSP90 inhibitors-mediated HSP70, while DcR2 protein is upregulated at transcriptional level in hypoxia state through HIF-1α signaling pathway. In our future study we plan to address the roles of both receptor induction in anti-tumor efficiency in response to TRAIL under HSP90 inhibitor treatment and hypoxia condition.

Abbreviations...………………………………………………………………………..1
Abstract………………………………………………………………………………..3
Abstract in Chinese…………..………………………………………………………..5
Introduction……………………………………………………………………………7
Specific Aims ………………………………………………………………..…….17
Meterials and Methods……………………………………………………………….18

PART I. HSP90 inhibitors Enhance TRAIL-induced cell apoptosis through DR5 upregulation: involvement of HSP70 upregulation.
Results………………………………………………………………..26
Discussion……...…………………………………………………….34
Figures….…………………………………………………………….39

PART II. Hypoxia induces DcR2 gene transcription through the hypoxia-inducible factor-1α upregulation.
Results………………………………………………………………..52
Discussion……...…………………………………………………….55
Figures..………………………………………………………………57

Reference……………………………………………………………..………………65

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