Matrine Reverses the Warburg Effect and Suppresses Colon Cancer Cell Growth via Negatively Regulating HIF-1α.

Xiaoting Hong,Yesen Li,Tianhui Hu,Daxuan Wang,Yan-Yan Zhan,Yurou Xie,Kaifeng Zheng,Linhai Zhong,Jinglong Pang,Xiaolin Xu,Wenqing Zhang,Gang Song,Hanwei Cao,Yifan Yang,Panying Mi

doi:10.3389/fphar.2019.01437

Abstract

The Warburg effect is a peculiar feature of cancer’s metabolism, which is an attractive therapeutic target that could aim tumor cells while sparing normal tissue. Matrine is an alkaloid extracted from the herb root of a traditional Chinese medicine, Sophora flavescens Ait. Matrine has been reported to have selective cytotoxicity toward cancer cells but with elusive mechanisms. Here, we reported that matrine was able to reverse the Warburg effect (inhibiting glucose uptake and lactate production) and suppress the growth of human colon cancer cells in vitro and in vivo. Mechanistically, we revealed that matrine significantly decreased the messenger RNA (mRNA) and protein expression of HIF-1α, a critical transcription factor in reprogramming cancer metabolism toward the Warburg effect. As a result, the expression levels of GLUT1, HK2, and LDHA, the downstream targets of HIF-1α in regulating glucose metabolism, were dramatically inhibited by matrine. Moreover, this inhibitory effect of matrine was significantly attenuated when HIF-1α was knocked down or exogenous overexpressed in colon cancer cells. Together, our results revealed that matrine inhibits colon cancer cell growth via suppression of HIF-1α expression and its downstream regulation of Warburg effect. Matrine could be further developed as an antitumor agent targeting the HIF-1α-mediated Warburg effect for colon cancer treatment.

Highlights

Cancer cells have remarkably increased metabolic requirements in comparison to normal cells
We found that matrine inhibited the transcription of HIF-1α, thereby reversing the Warburg effect and suppressing cell growth in human colon cancer cells in vitro and in vivo
Matrine inhibits the messenger RNA (mRNA) and protein expression of HIF-1α, thereby suppressing the transcription of glucose transporter 1 (GLUT1), HK2, and lactate dehydrogenase A (LDHA), the downstream targets of Hypoxia-induced factor 1 (HIF-1), which are the key enzymes involved in the glycolytic energy metabolism of cancer cells

Summary

Introduction

Cancer cells have remarkably increased metabolic requirements in comparison to normal cells. In order to support this demand, cancer cells consume much more glucose and produce lactic acid rather than catabolizing glucose by the tricarboxylic acid cycle. By this way, they would be able to consume additional nutrients and divert those nutrients into macromolecular synthesis pathways to support their rapid proliferation (Vander Heiden et al, 2009). They would be able to consume additional nutrients and divert those nutrients into macromolecular synthesis pathways to support their rapid proliferation (Vander Heiden et al, 2009) This phenomenon is termed as the “Warburg effect,” as first described by Otto Warburg in 1920s (Warburg, 1956). HIF-1α is accurately regulated by oxygen concentration while HIF-1β is constitutively

Methods

Results

Conclusion