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

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.

SUBMITTER: Yao C

PROVIDER: S-EPMC8790513 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Yao Chenguang C Weng Jun J Feng Lingyun L Zhang Wanjun W Xu Yan Y Zhang Peijing P Tanaka Yoshimasa Y Su Li L

Frontiers in cell and developmental biology 20220112

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 SIP ...[more]

PMID: 35096814

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Project description:Background: NOX4 is highly expressed in breast cancer and is closely associated with cell invasion and metastasis. The involvement of NOX4 in glycolysis in breast cancer remains unclear. The aim of this study was to investigate the role and mechanism of NOX4 in glycolysis in breast cancer. Methods: NOX4 expression in breast cancer cells was detected by qRT-PCR and western blotting. siRNAs and plasmids were used to silence or enhance the expression of NOX4. The mRNA and protein expression of HK2, GLUT1, PKM2, LDHA, and YAP was detected by qRT-PCR and western blotting, and the 18F-FDG uptake rate was detected by γ-radiometer. Detection of reactive oxygen species (ROS) in cells was performed using a commercial ROS kit. After transfection, CCK8, EDU and Transwell experiments were conducted to detect cell proliferation and migration ability. MicroPET imaging was used to detect the effects of NOX4 on tumor metabolism. Immunohistochemistry was used to detect the expression of NOX4, glycolytic enzymes HK2, GLUT1, PKM2, LDHA, the proliferation index KI67, and the activation of YAP pathway molecule. Results: In this study, the expression of NOX4 in MDA-MB-231 and MDA-MB-453 was higher than in MCF10A. qRT-PCR and western blotting experiments showed that NOX4 downregulation decreased the expression of glycolytic enzymes HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Conversely, the overexpression of NOX4 enhanced the expression of HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Proliferation and migration experiments showed that after down-regulation of NOX4, cell proliferation and migration ability decreased, while NOX4 overexpression promoted cell proliferation and migration ability. Additionally, ROS content and YAP expression decreased after NOX4 down-regulation, while ROS content and YAP expression increased following NOX4 overexpression, which was reversed by N-acetyl cysteine (NAC), a ROS inhibitor. Furthermore, exposure to NAC and Peptide17, a YAP inhibitor, blocked the increase in glycolytic enzyme expression, and the enhancement of proliferation and migration caused by NOX4 overexpression. In addition, in animal experiments, the results of the MicroPET imaging showed that the glucose metabolism rate of the NOX4 inhibitor group was significantly lower than that of the control group. ROS levels in the NOX4 inhibitor group was lower than that in the control group. Immunohistochemistry showed that the expression of HK2, GLUT1, PKM2, LDHA, KI67, and YAP in the NOX4 knock-down group were decreased. Conclusions: NOX4 affects breast cancer glycolysis through ROS-induced activation of the YAP pathway, further promoting the proliferation and migration of breast cancer cells.

Dataset Information

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

Publications

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

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