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01-12-2022 | Ovarian Cancer | Research

Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer

Authors: Shruthi Sriramkumar, Riddhi Sood, Thomas D. Huntington, Ahmed H. Ghobashi, Truc T. Vuong, Tara X. Metcalfe, Weini Wang, Kenneth P. Nephew, Heather M. O’Hagan

Published in: Journal of Translational Medicine | Issue 1/2022

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. Platinum treatment enriches for chemoresistant aldehyde dehydrogenase (ALDH) + ovarian cancer stem cells (OCSCs), which contribute to tumor recurrence and disease relapse. Acquired platinum resistance also 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 RT-qPCR. 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 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.

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Title: Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer
Authors: Shruthi Sriramkumar
Riddhi Sood
Thomas D. Huntington
Ahmed H. Ghobashi
Truc T. Vuong
Tara X. Metcalfe
Weini Wang
Kenneth P. Nephew
Heather M. O’Hagan
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Ovarian Cancer
Ovarian Cancer
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03447-y

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