Cisplatin-Resistant Ovarian Cancer Cells Reveal a Polyploid Phenotype with Remarkable Activation of Nuclear Processes.

Abstract

Tumor recurrence as one of the main causes of cancer death is a big barrier to cancer complete treatment. Various studies denote the possible role of therapeutics in tumor relapse. Cisplatin as one of the generally used chemotherapy agents is supposed to be the source of therapy resistance through formation of polyploid giant cancer cells (PGCCs). Nevertheless, the mechanisms by which PGCCs promote tumor relapse are not fully understood. In this study, we performed experimental and bioinformatic investigations to recognize the mechanisms related to cisplatin resistance. A2780 and SCOV-3 cell lines were treated with cisplatin for 72 hours and were evaluated for their morphology by fluorescent microscopy and DNA content analysis. Furthermore, a microarray dataset of cisplatin-resistant ovarian cancer cells was re-analyzed to determine the significantly altered genes and signaling pathways. Although cisplatin led to death of considerable fraction of cells in both cell lines, a significant number of survived cells became polyploid. On the other hand, our high throughput analysis determined significant change in expression of 1930 genes which mainly related to gene regulatory mechanisms and nuclear processes. Besides, mTOR, hypoxia, Hippo, and 14-3-3 signaling pathways previously shown to have role in PGCCs were determined. Taken together, results of this study demonstrated some key biological mechanisms related to cisplatin-resistant polyploid cancer cells.