Abstract
BackgroundTopotecan produces DNA damage that induces autophagy in cancer cells. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined.Methodology/Principal FindingsThe DNA damage induced by topotecan treatment resulted in cytoprotective autophagy in colon cancer cells with wild-type p53. However, in cells with mutant p53 or p53 knockout, treatment with topotecan induced autophagy-associated cell death. In wild-type p53 colon cancer cells, topotecan treatment activated p53, upregulated the expression of sestrin 2, induced the phosphorylation of the AMPKα subunit at Thr172, and inhibited the mTORC1 pathway. Furthermore, the inhibition of autophagy enhanced the anti-tumour effect of topotecan treatment in wild-type p53 colon cancer cells but alleviated the anti-tumour effect of topotecan treatment in p53 knockout cells in vivo.Conclusions/SignificanceThese results imply that the wild-type p53-dependent induction of cytoprotective autophagy is one of the cellular responses that determines the cellular sensitivity to the DNA-damaging drug topotecan. Therefore, our study provides a potential therapeutic strategy that utilises a combination of DNA-damaging agents and autophagy inhibitors for the treatment of colon cancer with wild-type p53.
Highlights
Topotecan, a topoisomerase I inhibitor that induces DNA damage, is used to treat colon cancer, ovarian cancer, lung cancer, and advanced cervical cancer [1,2]
LC3 is converted to lipidated LC3 (LC3-II) upon the formation of an autophagosome, and LC3-II migrates faster compared to the nonlipidated LC3-I on an SDS/PAGE gel [37]. We used this difference in migration to further monitor the LC3-II levels after topotecan treatment and found that the appearance of LC3-II was induced at a high level by topotecan treatment in a variety of colon cancer cell lines (Fig. 1B and Fig. S1)
The results revealed that P62 was degraded after topotecan treatment, which indicates autophagy was induced in these colon cancer cells (Fig. 1B and Fig. S1)
Summary
A topoisomerase I inhibitor that induces DNA damage, is used to treat colon cancer, ovarian cancer, lung cancer, and advanced cervical cancer [1,2]. Because the function of autophagy in cancers is complicated and may have opposing consequences[7], many hypotheses have been proposed regarding the role of autophagy in cancer One of these hypotheses suggests that the role of autophagy depends on the stage of tumour development[20]. Autophagy is localized to the hypoxic tumour regions that are the most distant from the nutrientsupplying blood vessels where it sustains tumour cell survival. Another hypothesis proposes that autophagy regulates cancer in a cell- and tissue-specific manner [21,22]. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined
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