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系統識別號 U0026-0812200915084613
論文名稱(中文) 缺氧調控丙酮酸去氫酶激酶及其對癌細胞抗藥性的影響之探討
論文名稱(英文) Regulation of pyruvate dehydrogenase kinase by hypoxia and its impact on drug resistance in cancer cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 97
學期 2
出版年 98
研究生(中文) 呂淳雯
研究生(英文) Chun-wun Lu
學號 s5893155
學位類別 博士
語文別 英文
論文頁數 86頁
口試委員 口試委員-洪文俊
口試委員-張智芬
口試委員-蔡坤志
口試委員-張文昌
口試委員-李碧雪
召集委員-黃步敏
指導教授-蔡少正
中文關鍵字 抗藥性  缺氧誘導因子  丙酮酸去氫酶激酶  代謝  缺氧 
英文關鍵字 drug resistance  metabolism  pyruvate dehydrogenase kinase  HIF  hypoxia 
學科別分類
中文摘要 細胞代謝由粒線體呼吸轉換為細胞質糖解作用對於癌細胞適應缺氧的環境是很重要的,然而,這種代謝轉換的機制目前仍不清楚。丙酮酸去氫酶激酶是一關鍵性的酵素,能藉由使丙酮酸去氫酶失去活性來抑制檸檬酸循環。我們假設缺氧可能會增加丙酮酸去氫酶激酶的表現量來抑制丙酮酸去氫酶的活性,進而抑制檸檬酸循環。研究結果發現在缺氧的環境下,丙酮酸去氫酶激酶1及3在某些癌細胞,例如子宮頸癌(HeLa)及大腸直腸癌(colo320 DM)細胞表現量會增加。利用生物資訊的方法分析人類丙酮酸去氫酶激酶的啟動子,結果發現在丙酮酸去氫酶激酶1-3的啟動子上存在著可能的缺氧反應元件。啟動子活性分析證實缺氧處理能促進丙酮酸去氫酶激酶1及3啟動子的活性,而此效果在突變了缺氧反應元件後則會消失。利用化學藥物模擬缺氧時能增加丙酮酸去氫酶激酶3啟動子的活性及表現。此外利用小干擾核糖核酸及染色體免疫沉澱分析進ㄧ步證實缺氧誘導因子-1α能調控丙酮酸去氫酶激酶3的表現。當丙酮酸去氫酶激酶3的表現增加時會導致細胞的乳酸累積及抗藥性。相反的,丙酮酸去氫酶激酶3的表現減少時則會抑制缺氧所促進的細胞質糖解作用及降低細胞存活。此外我們發現在子宮頸癌組織陣列切片和大腸直腸癌檢體中丙酮酸去氫酶激酶3的表現有增加的情形,而此情形與缺氧誘導因子-1α表現量增加呈現正相關,以上這些結果證實了在癌細胞中由於缺氧誘導因子-1α表現量增加而促使丙酮酸去氫酶激酶3的表現增加,而這樣的現象可能在癌症形成的過程中的代謝改變與癌細胞治療的抗藥性中扮演重要的角色。
英文摘要 The switch of cellular metabolism from mitochondrial respiration to cytoplasmic glycolysis is critical for the adaptation to hypoxia in tumor cells. However, the mechanism of this metabolic switch remains largely unknown. Pyruvate dehydrogenase kinase (PDK) is the enzyme that blocks tricarboxylic acid (TCA) cycle initiation by inactivating pyruvate dehydrogenase (PDH). We hypothesize that hypoxia may upregulate PDK, which in turn inactivates PDH and blocks the entry of TCA cycle. Here, we reported that the expressions of PDK1 and PDK3 were increased in several cancer cell lines, such as HeLa and colorectal cancer cell lines under hypoxia. Promoter activity assay demonstrated that hypoxia elevated PDK1 and PDK3 promoter activities and this effect was abolished by mutation of hypoxia response element. Chemical-mimicked hypoxia also induced the promoter activity and expression of PDK3. In addition, siRNA and chromatin immunoprecipitation assay provided further evidence that increased expression of PDK3 was mediated by HIF-1α. Forced expression of PDK3 in cancer cells resulted in increased lactic acid accumulation and drug resistance, whereas PDK3 knockdown inhibited hypoxia-induced cytoplasmic glycolysis and cell survival. Moreover, PDK3 expression was elevated in cervical cancer and colorectal cancer tissues. The level of PDK3 was correlated with the HIF-1α expression in colorectal cancer tissues. These data demonstrated that increased PDK3 expression due to elevated HIF-1α in cancer may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy
論文目次 Table of content
I. Literature review ................................... 1
1.1 Hypoxia incucible factor (HIF) .................. 1
1.1.1 HIF-1α and HIF-1β .......................... 1
1.1.2 The structure of HIF-α ............................ 1
1.1.3 Post-translational modification of HIF-1α ..... 2
1.1.4 The expression and gene regulation of HIF-1α and HIF-2α .................... 2
1.2 Cellular metabolism ................................. 3
1.2.1 Glucose metabolism in normal cells ...........3
1.2.2 Warburg effect ................................ 3
1. 3 Pyruvate dehydrogenase complex (PDC) ............... 4
1. 4 Pyruvate dehydrogenase kinase (PDK) ................ 4
1.4.1 The expression of PDK ............................ 5
1.4.2 The activity of PDK .......................... 5
1.5 Cervical cancer ..................................... 6
1.5.1 Overview of cervical cancer .................... 6
1.5.2 Risk factors of cervical cancer ....................6
1.5.3 Diagnosis and treatment of cervical cancer ........ 6
1.5.4 Prognosis of cervical cancer .................. 7
1.6 Colorectal cancer ............................. 7
1.6.1 Overview of colorectal cancer ..................... 7
1.6.2 Risk factors of colorectal cancer ................. 8
1.6.3 Diagnosis, treatment and prognosis of colorectal cancer .................................................. 8
1.7 HIF-1α in cervical and colorectal cancers ........... 8
1.8 Hypothesis ...........................................9
II. Materials and Methods ........................11
2.1 Cell culture and hypoxic treatment ................. 11
2.2 RNA isolation and real-time PCR .................... 11
2.3 Western Blotting .............................. 12
2.4 Plasmids, transfection, and promoter activity assay ................................................. 13
2.5 Small interference RNA (SiRNA) ................ 14
2.6 Chromatin immunoprecipitation (ChIP)-PCR assay .............................................. 15
2.7 Lactic acid assay ........................ 16
2.8 Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) Assay ........................... 16
2.9 Colorectal cancer tissues ....................... 17
2.10 Isolation of tissue protein ....................... 18
2.11 Immunohistochemistry (IHC) .........................18
2.12 Statistic analysis ......................... 19
III.Results .............................................23
3.1 Induction of PDK1 and PDK3 but not PDK2 and PDK4 by hypoxia ............ 23
3.2 Hypoxia-elevated PDK1 and PDK3 expression was a common phenomenon ..............................................24
3.3 Hypoxia regulates PDK1 and PDK3 expression through different mechanisms ............................24
3.4 Hypoxia-induced PDK3 expression is mediated by the direct binding of HIF-1α on the HRE of PDK3 promoter ..................................... 25
3.5 Lactic acid production was induced by elevated PDK3 ................................... 26
3.6 Hypoxia did not change the expression of PDP and PDH ............................... 26
3.7. Knocking down the expression of PDK3 did not change the level of HIF-1α ...................................26
3.8 Upregulation of PDK3 by hypoxia caused drug resistance ............................. 27
3.9 PDK1 and PDK3 additively increase drug resistance under hypoxia ............ 28
3.10 PDK3 expression was increased in cervical cancer tissues ............................ 28
3.11 The expression of PDK3 is increased whereas PDK1 is decreased in colorectal cancer tissues ................ 28
3.12 The elevated expression of HIF-1α in clinical colorectal caner tissues is correlated with the PDK3 expression ..............................................30
3.13 Hypoxia also induced PDK1 and PDK3 expression via HIF in colorectal cancer cell lines .......................31
3.14 Elevated expression of PDK3 by hypoxia also inhibited drug induced cell apoptosis in colorectal cancer cell .................................................. 32
IV. Discussion ..........................................61
V. Perspective ......................................... 68
VI. References......................................70
VII. Appendix ......................................... 81

List of tables
Table 1. Primer list ................................ 20
Table 2. Antibody list ............................... 21
Table 3. siRNA list ............................... 22
Table 4. Relation of PDK3 expression and various prognostic factors in 82 patients with colorectal cancer ................................................. 51
Table 5. Relation of HIF-1α expression and various prognostic factors in 82 patients with colorectal cancer .............................................. 54

List of figures
Figure 1. The promoter activities of PDK1 and PDK3 are induced by hypoxia. ......... 33
Figure 2. Hypoxia induces endogenous PDK1 and PDK3 mRNA expression. ........... 34
Figure 3. Endogenous PDK1 and PDK3 expressions are induced by chemical-accumulated HIF. ..................... 35
Figure 4. Hypoxia-induced PDK1 and PDK3 expression is a universal event in normal and cancer cells. ........36
Figure 5. HIF-1α and HIF-2α differently regulate PDK1 and PDK3 expression under hypoxia....................... 37
Figure 6. HIF-1α directly binds to HRE of PDK3 to induce its expression. ............... 38
Figure 7. Increased-production of lactic acid is attenuated in PDK3 knockdown cells. ................... 39
Figure 8. Forced-expression of PDK3 increases lactic acid production. ..................... 40
Figure 9. The expressions of PDP1, PDP2, and PDHβ2 are not changed by hypoxia in HeLa cells. ................... 41
Figure 10. The level of HIF-1α is not changed after knocking down the expression of PDK3. ................. 42
Figure 11. Hypoxia-induced drug resistance is attenuated by the siPDK3. ................. 43
Figure 12. Elevated expression of PDK3 increases drug resistance under normoxia. 44
Figure 13. PDK1 and PDK3 additively regulate HIF-induced drug resistance. ......... 45
Figure 14. The level of PDK3 is increased in cervical cancer tissues. ......................... 46
Figure 15. PDK3 expression is increased in colorectal cancer, whereas PDK1 is decreased. ................. 47
Figure 16. PDK3 is upregulated in the epithelial cells of colorectal cancer. ............... 49
Figure 17. HIF-1α expression is increased in colorectal cancer. ................................ 52
Figure 18. The level of HIF-1α is increased in the colorectal cancer. ........................ 53
Figure 19. The level of PDK3 is positively correlated with the level of HIF-1α in colorectal cancer. ............ 55
Figure 20. Hypoxia induces promoter activities of PDK1 and PDK3 in colo320 DM cells. .......................... 56
Figure 21. The expression of PDK1 and PDK3 are also induced by hypoxia in the other colorectal cancer cells. ................................................ 57
Figure 22. Forced expression of HIF-1α increases PDK1 and PDK3 expression. ..... 58
Figure 23. PDK3 also involves in the hypoxia-induced drug resistance in colorectal cancer cell. ............... 59
Figure 24. Schematic drawing presents a model of hypoxia or HIF in PDK expression and the downstream effects on metabolic switch and drug resistance in colorectal cancer. ................................... 60
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