Platinum-Induced Mitochondrial OXPHOS Contributes to Cancer Stem Cell Enrichment in Ovarian Cancer

Abstract

Background: Platinum based agents cisplatin and carboplatin in combination with taxanes are used for the treatment of ovarian cancer (OC) patients. However, the majority of OC patients develop recurrent, platinum resistant disease that is uniformly fatal. Acute platinum treatment enriches for chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSCs), which contribute to tumor recurrence and disease relapse. Acquired platinum resistance includes metabolic reprograming and switching to oxidative phosphorylation (OXPHOS). Chemosensitive cells rely on glycolysis while chemoresistant cells have the ability to switch between glycolysis and OXPHOS, depending on which pathway drives a selective advantage for growth and chemoresistance. High expression of genes involved in OXPHOS and high production of mitochondrial ROS are characteristics of OCSCs, suggesting that OCSCs favor OXPHOS over glycolysis. Based on connections between OCSCs, chemoresistance and OXPHOS, we hypothesize that platinum treatment induces changes in metabolism that contribute to platinum-induced enrichment of OCSCs. Methods: The effect of cisplatin on mitochondrial activity was assessed by JC1 staining and expression of OXPHOS genes by quantitative RTPCR. Cisplatin-induced changes in Sirtuin 1 (SIRT1) levels and activity were assessed by Western blot. Small molecule inhibitors of mitochondrial complex I and SIRT1 were used to determine if their enzymatic activity contributes to the platinum-induced enrichment of OCSCs. The percentage of ALDH+ OCSCs in OC cells and tumor tissue from xenograft models across different treatment conditions was analyzed using ALDEFLUOR assay and flow cytometry. Results: We demonstrate that acute platinum treatment increases mitochondrial activity. Combined treatment of platinum agents and OXPHOS inhibitors blocks the platinum-induced enrichment of ALDH+ OCSCs in vitro and in vivo. Furthermore, platinum treatment increases SIRT1 levels and subsequent deacetylase activity, which likely contributes to the increase in platinum-induced mitochondrial activity. Conclusions: These findings on metabolic pathways altered by platinum-based chemotherapy have uncovered key targets that can be exploited therapeutically to block the platinum-induced enrichment of OCSCs, ultimately improving the survival of OC patients.

Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors

“…CD177+ cells overexpress ABCG2, conferring cisplatin and paclitaxel resistance, while CD24 expression induces EMT and cisplatin resistance in OC OC [117,118] . CD44 and ALDH1A1+ OCSCs confer platinum and taxane resistance, with ALDH1 silencing sensitizing cells to chemotherapy [119][120][121][122] . The platinum treatment induces OCSC proliferation, blocked by a combination of platinum and oxidative phosphorylation (OXPHOS) inhibitors [123] .…”

UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

“…In OV90 cells, the reduction of viability caused by UGDH knockdown in spheroids may explain the overall reduction in CD133+/ALDH high cells. And in ACI23, overexpression of UGDH may out-compete ALDH for NAD+ substrate, as both are dependent on this for activity (16,49), thus causing reduced ALDH activity to be observed. Finally, we used our previously reported in vitro relapse model (30,50) to directly assess the potential for spheroids with altered UGDH to promote growth and persist after chemotherapy.…”