SIPA1 Enhances Aerobic Glycolysis Through HIF-2α Pathway to Promote Breast Cancer Metastasis.

Chenguang Yao,Yan Xu,Yoshimasa Tanaka,Jun Weng,Lingyun Feng,Peijing Zhang,Li Su,Wanjun Zhang

doi:10.3389/fcell.2021.779169

Abstract

Increased dependence on aerobic glycolysis is characteristic of most cancer cells, whereas the mechanism underlying the promotion of aerobic glycolysis in metastatic breast cancer cells under ambient oxygen has not been well understood. Here, we demonstrated that aberrant expression of signal-induced proliferation-associated 1 (SIPA1) enhanced aerobic glycolysis and altered the main source of ATP production from oxidative phosphorylation to glycolysis in breast cancer cells. We revealed that SIPA1 promoted the transcription of EPAS1, which is known as the gene encoding hypoxia-inducible factor-2α (HIF-2α) and up-regulated the expression of multiple glycolysis-related genes to increase aerobic glycolysis. We also found that blocking aerobic glycolysis by either knocking down SIPA1 expression or oxamate treatment led to the suppression of tumor metastasis of breast cancer cells both in vitro and in vivo. Taken together, aberrant expression of SIPA1 resulted in the alteration of glucose metabolism from oxidative phosphorylation to aerobic glycolysis even at ambient oxygen levels, which might aggravate the malignancy of breast cancer cells. The present findings indicate a potential target for the development of therapeutics against breast cancers with dysregulated SIPA1 expression.

Highlights

Cancer cells rely on aerobic glycolysis for energy resources, even under the condition of ambient oxygen levels (Hanahan and Weinberg, 2011)
To verify the correlation between signal-induced proliferation-associated 1 (SIPA1) and aerobic glycolysis, we established MDA-MB-231 and BT549 cell lines expressing a low level of SIPA1 and an MCF7 cell line overexpressing a high level of SIPA1 (MCF7/SIPA1) (Figure 1A and Supplementary Figure S2A), and we found knocking down SIPA1 decreased the levels of lactate production and glucose consumption, whereas forced expression of SIPA1 exhibited the opposite effects in these cells (Figures 1B,C and Supplementary Figures S2B–C)
Since lactate dehydrogenase A (LDHA) is a critical enzyme for the conversion of pyruvate to lactate at the final step of aerobic glycolysis, we set out to determine whether lactate dehydrogenase (LDH) activity was modulated by SIPA1 in breast cancer cells

Summary

Introduction

Cancer cells rely on aerobic glycolysis for energy resources, even under the condition of ambient oxygen levels (Hanahan and Weinberg, 2011). By inducing glycolysis-related genes products such as hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and glucose transporter 1 (GLUT1, known as solute carrier family A1, SLC2A1), HIF-1α switches the glucose metabolism of hypoxic tumor cells to the glycolytic pathway This metabolic switch might cause a shift in energy production in cancer cells (Denko, 2008). It has been reported that HIF-2α activates c-myc in a way that mimics a response to hypoxia and triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in an increase in glutamine uptake and catabolism in SiHa and HeLa cervical carcinoma cells (Perez-Escuredo et al, 2016) These regulators have been shown to be responsible for aerobic glycolysis, the precise mechanism how breast cancer cells switch this metabolic process has not been well delineated yet

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