AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth.

Xunzhe Yin,Huaxing Cai,Zuojia Liu,Jin Wang,Wenjing Zhao,Yan Guo,Chi Zhang,Wenbo Li,Jiaxin Zhang

doi:10.3390/metabo11120811

Abstract

Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (l-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, l-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to l-THP treatment. More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common cancer, accounting for the fourth highest mortality rate worldwide [1]
Inhibition of mitochondrial metabolism facilitates the generation of reactive oxygen species (ROS), whereas oxidative phosphorylation (OXPHOS) impairment leads to phosphorylation-related changes in the ROS-mediated extracellular signal-regulated kinase (ERK)/serine-threonine kinase (AKT) pathway
Global quantification of the metabolic landscape is a promising strategy to clarify the potential mechanisms of cancer metabolism

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer, accounting for the fourth highest mortality rate worldwide [1]. Autophagy is an intracellular evolutionarily conserved catabolic degradation process involving the proteins or damaged organelles [3] These cytoplasmic macromolecules are delivered to lysosomes and digested, producing basal buildings for cellular energy metabolism. This cellular self-digestion effectively maintains cellular homeostasis and mitigates metabolic stress under normal growth conditions. Inhibition of mitochondrial metabolism facilitates the generation of reactive oxygen species (ROS), whereas OXPHOS impairment leads to phosphorylation-related changes in the ROS-mediated extracellular signal-regulated kinase (ERK)/serine-threonine kinase (AKT) pathway. These alterations contribute to the initiation or progression of cancer [7]. Understanding the detailed mechanisms underlying such altered metabolism will be beneficial for cancer treatment [8]

Methods

Results

Conclusion