PKM2 Promotes Cell Survival and Invasion Under Metabolic Stress by Enhancing Warburg Effect in Pancreatic Ductal Adenocarcinoma.
BACKGROUND
Pyruvate kinase isoenzyme M2 (PKM2) is an essential enzyme involved in the regulation of aerobic glycolysis in cancer cells and promotes the translation between glycolytic flux and biosynthesis of cellular building blocks.


OBJECTIVE
Our present study aims to explore the expression pattern and underlying cellular functions of PKM2 in pancreatic ductal adenocarcinoma (PDAC) under metabolic stress.


METHODS
Oncomine database and a tissue microarray (n = 90) were used to investigate the expression pattern of PKM2 and its clinicopathological findings. In vitro proliferation, apoptosis and invasion assays were used to determine the role and related mechanism of PKM2 in PDAC.


RESULTS
Data from Oncomine database and our tissue microarray show that PKM2 is significantly elevated in PDAC specimens compared with the corresponding normal tissues. Kaplan-Meier survival analysis shows that higher expression of PKM2 is closely correlated with a poor prognosis of patients with PDAC. Under metabolic stress, suppression of PKM2 expression in PANC-1 and AsPC-1 cells results in decreased cell survival, increased caspase-3/7 activity, and reduced invasive potential, and these effects can be reversed by reintroduction of PKM2. Furthermore, sh-PKM2 cells show a significant decreased Warburg effect compared with sh-Ctrl cells as demonstrated by reduced glucose consumption and lactate production. Treatment with 2-deoxy-D-glucose, a glycolysis inhibitor, completely blocks the influences of PKM2 on cell survival and invasion.


CONCLUSIONS
Our study reveals that silencing of PKM2 exhibits a tumor-suppressive role through altered Warburg effect and suggests that targeting PKM2 might serve as a potential therapeutic target for PDAC.
Department of Surgical Oncology, Chinese PLA General Hospital, 28#, Fuxing Road, Beijing, 100853, People's Republic of China. drchengg@126.com.
Chenggang
C
Li
Department of Surgical Oncology, Chinese PLA General Hospital, 28#, Fuxing Road, Beijing, 100853, People's Republic of China.
Zhiming
Z
Zhao
Department of Surgical Oncology, Chinese PLA General Hospital, 28#, Fuxing Road, Beijing, 100853, People's Republic of China.
Zhipeng
Z
Zhou
Department of Surgical Oncology, Chinese PLA General Hospital, 28#, Fuxing Road, Beijing, 100853, People's Republic of China.
Rong
R
Liu
D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D013312:Stress, Physiological / Q000235:genetics*; D015996:Survival Rate; D013963:Thyroid Hormones / Q000235:genetics*; D000097810:Thyroid Hormone-Binding Proteins
D002352:Carrier Proteins; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose; D008565:Membrane Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C505407:CASP3 protein, human; C505520:CASP7 protein, human
Invasion; PKM2; Pancreatic ductal adenocarcinoma; Survival; Warburg effect