Adaptation to endoplasmic reticulum stress enhances resistance of oral cancer cells to cisplatin by up-regulating polymerase η and increasing DNA repair efficiency

Cho Yi Chen, Masaoki Kawasumi, Tien Yun Lan, Chi Lam Poon, Yi Sian Lin, Pin Jou Wu, Yao Chung Chen, Bing Hong Chen, Cheng Hsien Wu, Jeng Fan Lo, Rueyhung Roc Weng, Yi Chen Sun, Kai Feng Hung*

*此作品的通信作者

研究成果: Article同行評審

7 引文 斯高帕斯(Scopus)

摘要

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal-epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.

原文English
文章編號355
頁(從 - 到)1-21
頁數21
期刊International Journal Of Molecular Sciences
22
發行號1
DOIs
出版狀態Published - 1 1月 2021

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