The responsively decreased PKM2 facilitates the survival of pancreatic cancer cells in hypoglucose.

Abstract

Cancer cells predominantly produce energy at a high rate of glycolysis even in aerobic environment. It is termed as Warburg effect and is necessary for the tumorigenesis. Studies showed pyruvate kinase M2 (PKM2), a key regulator of the Warburg effect, is overexpressed and involved in numerous cancers. However, the expression and function of PKM2 in pancreatic cancer (PC) remain undefined. Our results showed that PKM2 is overexpressed in the PC tissue compared to the peritumoral tissue. Unexpected, the downregulation of PKM2 did not affect the proliferation, invasion, and chemoresistance of PC cells. Since pancreatic cancer is a hypovascular tumor with comparably insufficient energy supply, we further investigate the relationship between PKM2 and hypoglucose. Interestingly, we further discovered that decreased expression of PKM2 was detected in PC samples with lower microvessel density as well as in PC cells treated with hypoglucose condition (0.5 mM). Furthermore, the downregulation of PKM2 facilitated, while the upregulation of PKM2 inhibited, PC cells survival during hypoglucose. We further revealed that the repressed PKM2 induced autophagy, high NADPH/NADP ratio, and biomacromolecule production, but reduced ROS accumulation. Moreover, AMPKα1 knockdown repressed the autophagy and survival of PC cells during hypoglucose, which were promoted by PKM2 knockdown. Collectively, our study indicates that decreased PKM2 diverts glucose metabolism to biomacromolecule accumulation and antioxidants generation during glucose deprivation. This metabolism alteration elevates AMPKα1-dependent autophagy, which facilitates PC cell survival during glucose deprivation. Therefore, functions of PKM2 are complicated and cannot be defined as oversimplified promoter or inhibitor in PC.

• Authors: Xiang Li, Shichang Deng, Mingliang Liu, Yan Jin, Shuai Zhu, Shijiang Deng, Jingyuan Chen, Chi He, Qi Qin, Chunyou Wang, Gang Zhao
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 2 Pg. 133 (01 26 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29374159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Membrane Proteins
• Reactive Oxygen Species
• Thyroid Hormones
• thyroid hormone-binding proteins
• Lactic Acid
• Proto-Oncogene Proteins c-akt
• Adenylate Kinase
• Sirtuin 1
• Glucose

Topics

• Adenylate Kinase (metabolism)
• Autophagy (drug effects)
• Carrier Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glucose (pharmacology)
• Humans
• Lactic Acid (biosynthesis)
• Membrane Proteins (genetics, metabolism)
• Neoplasm Invasiveness
• Pancreatic Neoplasms (enzymology, genetics, pathology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Sirtuin 1 (metabolism)
• Thyroid Hormones (genetics, metabolism)
• Tumor Microenvironment (drug effects)
• Up-Regulation (drug effects)