Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways.

Li Yang,Xi Tang,Mingli Zhou,Qing Zhu,Manran Liu,Liyun Xu,Shifu Tang,Jie Yuan,Hailong Zhang,Xiaojiang Cui,Yan-E Du,Yixuan Hou,Siyang Wen

doi:10.18632/oncotarget.4697

Abstract

Twist, a key regulator of epithelial-mesenchymal transition (EMT), plays an important role in the development of a tumorigenic phenotype. Energy metabolism reprogramming (EMR), a newly discovered hallmark of cancer cells, potentiates cancer cell proliferation, survival, and invasion. Currently little is known about the effects of Twist on tumor EMR. In this study, we found that glucose consumption and lactate production were increased and mitochondrial mass was decreased in Twist-overexpressing MCF10A mammary epithelial cells compared with vector-expressing MCF10A cells. Moreover, these Twist-induced phenotypic changes were augmented by hypoxia. The expression of some glucose metabolism-related genes such as PKM2, LDHA, and G6PD was also found to be upregulated. Mechanistically, activated β1-integrin/FAK/PI3K/AKT/mTOR and suppressed P53 signaling were responsible for the observed EMR. Knockdown of Twist reversed the effects of Twist on EMR in Twist-overexpressing MCF10A cells and Twist-positive breast cancer cells. Furthermore, blockage of the β1-integrin/FAK/PI3K/AKT/mTOR pathway by siRNA or specific chemical inhibitors, or rescue of p53 activation can partially reverse the switch of glucose metabolism and inhibit the migration of Twist-overexpressing MCF10A cells and Twist-positive breast cancer cells. Thus, our data suggest that Twist promotes reprogramming of glucose metabolism in MCF10A-Twist cells and Twist-positive breast cancer cells via activation of the β1-integrin/FAK/PI3K/AKT/mTOR pathway and inhibition of the p53 pathway. Our study provides new insight into EMR.

Highlights

Most cancer cells tend to utilize aerobic glycolysis to produce energy instead of oxidative phosphorylation even in the presence of abundant oxygen
We evaluated whether energy metabolism reprogramming (EMR) is regulated by Twist in MCF10A-Twist and Twist-positive breast cancer cells
We found that the expression of Twist resulted in an altered energy metabolic phenotype of MCF10A-Twist and Twist-positive breast cancer BT549 cells

Summary

Introduction

Most cancer cells tend to utilize aerobic glycolysis to produce energy instead of oxidative phosphorylation even in the presence of abundant oxygen. This phenomenon was first described by Otto Warburg and termed as Warburg effect [1]. It has been shown that abnormal expression of these enzymes could contribute to promote Warburg effect in cancer cells [8,9,10,11]. Cancer cells reprogram their metabolism to facilitate fast proliferation through increased glycolysis and biosynthetic activities. The key molecular mechanisms for EMR regulation and its role in cancer development still remain elusive

Methods

Results

Conclusion