Expression of Ferredoxin1 in cisplatin-resistant ovarian cancer cells confers their resistance against ferroptosis induced by cisplatin

Sep 28, 2026

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Ovarian cancer is a refractory disease with relapse driven by acquisition of resistance to anticancer drugs, including cisplatin, yet the molecular basis of this resistance remains unclear. This study used parental A2780 and OVK18 lines and their cisplatin-resistant derivatives to show that cisplatin triggers ferroptosis via enhanced mitochondrial membrane potential and lipid peroxidation. Ferredoxin1 (Fdx1) was upregulated in resistant cells without cisplatin, and siRNA depletion of Fdx1 intensified cisplatin-induced ferroptosis by further increasing mitochondrial membrane potential and lipid peroxidation. Higher Fdx1 expression was also detected in clinical cisplatin-resistant specimens than in cisplatin-sensitive ones, supporting Fdx1 as a potential biomarker and therapeutic target.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

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Introduction

Clinical context of ovarian cancer and cisplatin resistance

Ferroptosis and its cancer relevance

Role of iron-sulfur proteins and Ferredoxin1 (Fdx1)

Study design and key findings

Cisplatin-induced ferroptosis in parental cells

Fdx1 upregulation in cisplatin-resistant cells

Effects of Fdx1 depletion on ferroptosis

Fdx1 expression in patient specimens

ONCOLOGY REPORTS 49: 124, 2023 Expression of Ferredoxin1 in cisplatin‑resistant ovarian cancer cells confers their resistance against ferroptosis induced by cisplatin RYOSUKE TAKAHASHI 1,2 , KOKI KAMIZAKI 1 , KEITARO YAMANAKA2 , YOSHITO TERAI2 and YASUHIRO MINAMI 1 1Division of Cell Physiology, Department of Physiology and Cell Biology; 2Department of Obstetrics and Gynecology, Graduate School of Medicine, Kobe University, Kobe 650‑0017, Japan Received January 13, 2023; Accepted March 7, 2023 DOI: 10. 3892/or.2023.8561 Abstract. Ovarian cancer (OC) is a refractory cancer that shows recurrence due to the acquisition of resistance to anticancer drugs, including cisplatin. However, the molecular mechanism underlying the acquisition of cisplatin resistance by cancer cells remains largely unknown. In the present study, two sets of ovarian endometrioid carcinoma cell lines were used: The parental A2780 cell line, the OVK18 cell line, and their derived cisplatin‑resistant cells. It was found that cisplatin could induce ferroptosis in these parental cells by enhancing mitochondrial membrane potential and lipid peroxidation as assessed by flow cytometric analysis, and that expression of Ferredoxin1 (Fdx1), an iron‑sulfur protein localized to the mitochondria, could be upregulated in cisplatin‑resistant cells in the absence of cisplatin. Intriguingly, it was shown that the siRNA‑mediated depletion of Fdx1 in cisplatin‑resistant cells resulted in enhanced ferroptosis by increasing the mitochon‑ drial membrane potential and lipid peroxidation induced by cisplatin. By examining Fdx1 expression with immunohisto‑ chemical analysis in clinical specimens from patients with OC, higher expression of Fdx1 was detected in cisplatin‑resistant specimens than in cisplatin‑sensitive specimens. Collectively, these results indicated that Fdx1 may be a novel and suitable Correspondence to: Dr Koki Kamizaki or Professor Yasuhiro Minami, Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7‑5‑1 Kusunoki‑cho, Chuo‑ku, Kobe 650‑0017, Japan E‑mail: pelican@med.kobe‑[u.ac.jp](u.ac.jp) E‑mail: minami@kobe‑[u.ac.jp](u.ac.jp) Abbreviations: A2780cis cells, cisplatin‑resistant A2780 cells; CCK‑8, Cell Counting Kit‑8; DEG, differentially expressed gene; Fdx1, Ferredoxin1; FSP1, ferroptosis suppressor protein 1; GPX4, glutathione peroxidase 4; OC, ovarian cancer; OVK18cis cells, cisplatin‑resistant OVK18 cells; TMA, tissue microarray Key words: ovarian cancer, cisplatin resistance, Ferredoxin1, ferroptosis, mitochondria diagnostic/prognostic marker and therapeutic molecular target for the treatment of cisplatin‑resistant OC. Introduction Ovarian cancer (OC) has high morbidity and mortality rates, and age‑standardized mortality is the highest among gynecological cancers worldwide (1) . As patients are often asymptomatic,>40% of cases are advanced at diagnosis, and the treatment strategy is debulking surgery followed by chemotherapy (2) . First‑line chemotherapy is a combination of carboplatin and paclitaxel (3), and the response to platinum agents contributes the most to therapeutic efficacy. OC has a very high recur‑ rence rate and is classified as a platinum‑resistant tumor if it recurs within 6 months of completing platinum‑based chemotherapy (4) . In patients with platinum‑resistant tumors, the response rate to other chemotherapies is 10‑15%, and the overall survival is within 12 months (5) . In recent years, the effectiveness of molecular‑targeted therapy, including immu‑ notherapy, for platinum‑resistant tumors has been reported, but treatment strategies have not yet been established (6,7) . Ferroptosis is defined as iron‑dependent cell death due to the accumulation of lipid hydroperoxides, and is distinguished from apoptosis and necroptosis (8,9) . Accumulating evidence has shown that ferroptosis plays an important role in patho‑ logical conditions and diseases, inc

FAQs

Why is cisplatin resistance a major challenge in ovarian cancer?

Ovarian cancer frequently recurs and is categorized as platinum-resistant when it returns within 6 months after platinum-based chemotherapy. In platinum-resistant tumors, responses to other chemotherapies are low and overall survival is limited.

How does cisplatin induce ferroptosis in ovarian cancer cells?

Cisplatin enhances mitochondrial membrane potential and lipid peroxidation, leading to ferroptosis in parental A2780 and OVK18 cells.

What role does Ferredoxin1 (Fdx1) play in cisplatin-resistant cells?

Fdx1 expression increases in cisplatin-resistant cells even without cisplatin. Depleting Fdx1 by siRNA enhances cisplatin-induced ferroptosis, indicating that Fdx1 supports resistance.

Sep 28, 2026

Uploaded by Aurelia