Schematic depiction of the association between the platinum distribution in tumor cells and platinum resistance in ovarian cancer. (IMAGE)
Caption
Low expression of CTR1 or high expression of CTR2 leads to impaired cisplatin uptake. Partial cisplatin taken up via CTR1 are transferred to ATOX1. Increased intracellular cisplatin induces the expression of ATOX1. ATOX1 can induce the polyubiquitination and down-regulation of CTR1, leading to reduced cisplatin uptake. Besides, ATOX1 transfers cisplatin to ATP7A/B and ATP11B in the secretory pathway, which leads to the sequestration and extrusion of cisplatin in vesicular compartments. Intriguingly, exposure to platinum agents promotes the entry of ATOX1 into the nucleus to increase the transcription of MDC1, thereby promoting DNA damage repair. Moreover, GSH and MTs can bind to cisplatin, leading to its inactivation.
Credit
He Li, Jia-Jia Sheng, Sheng-An Zheng, Po-Wu Liu, Nayiyuan Wu, Wen-Jing Zeng, Ying-Hua Li, Jing Wang
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CC BY-NC-ND