癌細胞中調控CCT-β表現程度對伴侶蛋白折疊與抗藥性之影響

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癌細胞中調控CCT-β表現程度對伴侶蛋白折疊與抗藥性之影響

Regulating CCT-β expression level affects chaperonin folding machinery and drug resistance in cancer cell

趙哲寬 , Masters　　Advisor：梁博煌　　

英文

抗藥性癌症細胞；多重抗藥性蛋白；伴侶蛋白；細胞骨架；新藥開發； chaperonin ； CCT-β ； Multidrug resistance protein 1 ； tubulin

Abstract │ Reference (13) │ Altmetrics

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Chaperonin containing t-complex polypeptide 1 (CCT) is a molecular chaperonin that facilitates the protein folding process in eukaryotic cytosol. The expression level of the CCT-β subunit was found elevated in a variety of drug-resistant tumor types (Lin et al., 2009). In this study, the main purpose is to examine the characteristics of up-regulating CCT-β in cancer cells.
	Initially, the classic substrates of CCT, actin and tubulin, were examined. Overexpression of CCT-β resulted in significantly elevated expression of both molecules, while knockdown of CCT-β gave no apparent difference. Therefore, up-regulation of CCT-β in cancer cells promotes more vigorous cytoskeleton formation.
	Next, other subunits of CCT were examined. In both CCT-β overexpress and knockdown stable clone, as well as paclitaxel-resistant cells, some but not all of the eight subunits were found to have synchronous changes with CCT-β in final protein amount. This phenomenon could be explained by the sub-assemblies during the complete CCT complex formation. Abnormally high level of CCT-β in cancer cells may hence break the balance of CCT subunits and affect the folding efficiency.
	On the other hand, expression level of CCT-β also correlated with the phosphorylation of Elk1, a transcription factor which is usually activated by MAPK family member p38. CCT-β up-regulation was found to induce the multi-drug resistance in cancer cells and stable clone, and the expression of multidrug-resistant protein (MDR1) was induced by CCT-β up-regulation. RNA interference experiments revealed that Elk1 knockdown effectively repressed MDR1 expression and drug resistance in CCT-β up-regulated cells. Interestingly, CCT-β seemed able to affect the phosphorylation level of Elk1, indicating that MDR1 expression and drug resistance in cancer cells may be controlled by MAPK signaling and stress-induced CCT-β.
	Moreover, a recently screened compound called R379603 showed significant apoptosis effects on CCT-β up-regulated cancer cells. R379603 led to CCT-β up-regulated cell death by introducing ER stress in cells, causing caspase activation and apoptosis. Since this is the route bypassing MDR1-related drug resistance, R379603 may therefore be a promising candidate for treating patients with elevated CCT-βand MDR1 expression.
	Overall, these studies uncovered two possible roles of CCT-β in CCT-β up-regulated cancer cells: enhancing folding efficiencies of cytoskeleton molecules, and inducing multi-drug resistance. Since CCT-β may be leading CCT assembly and substrate folding, the importance of CCT-β should be further investigated.

Reference ( 13 ) 〈TOP〉

Abe Y, Yoon SO, Kubota K, Mendoza MC, Gygi SP, Blenis J (2009) p90 Ribosomal S6 Kinase and p70 Ribosomal S6 Kinase Link Phosphorylation of the Eukaryotic Chaperonin Containing TCP-1 to Growth Factor, Insulin, and Nutrient Signaling. J Biol Chem. 284(22), 14939–14948.
連結：
Baguley BC (2010) Multiple Drug Resistance Mechanisms in Cancer. Mol Biotechnol 46, 308–316.
連結：
Besnard A, Galan-Rodriguez B, Vanhoutte P, Caboche J (2011) Elk-1 a transcription factor with multiple facets in the brain. Front Neurosci. 5, 1-11.
連結：
Bradley G, Ling V (1994) P-glycoprotein, multidrug resistance and tumor progression. Cancer Metast Rev. 13, 223-233.
連結：
Camasses A, Bogdanova A, Shevchenko A, Zachariae W (2003) The CCT Chaperonin Promotes Activation of the Anaphase-Promoting Complex through the Generation of Functional Cdc20 (2003) Mol cell. 12, 87–100
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