Hypoxia promotes the growth and metastasis of ovarian cancer cells by suppressing ferroptosis via upregulating SLC2A12

Mingmei Li; Li Li; Xiaoxiao Cheng; Longyu Li; Kaijia Tu

doi:10.1016/j.yexcr.2023.113851

Hypoxia promotes the growth and metastasis of ovarian cancer cells by suppressing ferroptosis via upregulating SLC2A12

Exp Cell Res. 2023 Dec 15;433(2):113851. doi: 10.1016/j.yexcr.2023.113851. Epub 2023 Nov 6.

Authors

Mingmei Li¹, Li Li¹, Xiaoxiao Cheng¹, Longyu Li², Kaijia Tu³

Affiliations

¹ Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 508 Xizhan Street, Nanchang, Jiangxi, China.
² Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 508 Xizhan Street, Nanchang, Jiangxi, China. Electronic address: lilongyu1103@sina.com.
³ Department of Oncology, Jiangxi Maternal and Child Health Hospital, No. 508 Xizhan Street, Nanchang, Jiangxi, China. Electronic address: tukaijia@sina.com.

PMID: 37940066
DOI: 10.1016/j.yexcr.2023.113851

Abstract

Background: Ovarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer.

Method: MTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo.

Results: Hypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo.

Conclusion: Hypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.

Keywords: Ferroptosis; Glutathione metabolism; Hypoxia; SLC2A12; ovarian cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Female
Ferroptosis* / genetics
Glucose Transport Proteins, Facilitative* / genetics
Glucose Transport Proteins, Facilitative* / metabolism
Glutathione
Humans
Hypoxia
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Ovarian Neoplasms* / pathology

Substances

Glutathione
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
SLC2A12 protein, human
Glucose Transport Proteins, Facilitative