Abstract
BackgroundWhile most cancer cells preferentially express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), PKM2 is dispensable for tumor development in several mouse cancer models. PKM2 is expressed in human pancreatic cancer, and there have been conflicting reports on the association of PKM2 expression and pancreatic cancer patient survival, but whether PKM2 is required for pancreatic cancer progression is unknown. To investigate the role of PKM2 in pancreatic cancer, we used a conditional allele to delete PKM2 in a mouse model of pancreatic ductal adenocarcinoma (PDAC).ResultsPDAC tumors were initiated in LSL-KrasG12D/+;Trp53flox/flox;Pdx-1-Cre (KP−/−C) mice harboring a conditional Pkm2 allele. Immunohistochemical analysis showed PKM2 expression in wild-type tumors and loss of PKM2 expression in tumors from Pkm2 conditional mice. PKM2 deletion had no effect on overall survival or tumor size. Loss of PKM2 resulted in pyruvate kinase M1 (PKM1) expression, but did not affect the number of proliferating cells. These findings are consistent with results in other cancer models.ConclusionsPKM2 is not required for initiation or growth of PDAC tumors arising in the KP−/−C pancreatic cancer model. These findings suggest that, in this mouse PDAC model, PKM2 expression is not required for pancreatic tumor formation or progression.
Highlights
Pyruvate kinase is an enzyme that catalyzes the final step of glycolysis to convert phosphoenolpyruvate and ADP to pyruvate and ATP
Compared to the normal pancreas, end-stage pancreatic ductal adenocarcinoma (PDAC) tumors from LSL-KrasG12D/+; Trp53flox/flox;Pdx-1-Cre (KP−/−C) [32] (Fig. 1a) or LSL-KrasG12D/+;LSL–Trp53R172H/+;Pdx-1-Cre (KPC) [33] (Additional file 1: Figure S1A) mice showed increased staining for Pyruvate kinase (PKM2) and minimal pyruvate kinase M1 (PKM1) staining
Flox tumors may downregulate expression of pyruvate kinase to enable tumor growth. These results argue that PKM2 expression has no significant effect on tumor initiation or progression in a mouse pancreatic cancer model driven by mutant Kras and
Summary
While most cancer cells preferentially express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), PKM2 is dispensable for tumor development in several mouse cancer models. Loss of PKM2 resulted in pyruvate kinase M1 (PKM1) expression, but did not affect the number of proliferating cells. These findings are consistent with results in other cancer models. Conclusions: PKM2 is not required for initiation or growth of PDAC tumors arising in the KP−/−C pancreatic cancer model. These findings suggest that, in this mouse PDAC model, PKM2 expression is not required for pancreatic tumor formation or progression
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