Abstract
The M2 isoform of pyruvate kinase (PKM2) is a key driver of glycolysis in cancer cells and has critical ‘non-metabolic’ functions in some cancers; however, the role of PKM2 in pancreatic cancer remains unclear. The aim of the current study was to elucidate the role of PKM2 in pancreatic cancer progression and the potential of PKM2 as a therapeutic target. In this study, we observed that PKM2 is highly expressed in patients with pancreatic cancer and is correlated to survival. Elevated PKM2 expression promoted cell proliferation, migration and tumor formation. The inhibition of cell growth by silencing PKM2 is caused by impairment of the autophagy process. To test the potential effects of downregulating PKM2 as a clinical therapy, we constructed an RGD-modified oncolytic adenovirus containing shPKM2 (OAd.R.shPKM2) to knock down PKM2 in pancreatic cancer cells. Cells transduced with OAd.R.shPKM2 exhibited decreased cell viability, and, in a PANC-1 xenograft model, intratumoral injection of OAd.R.shPKM2 resulted in reduced tumor growth. Furthermore, OAd.R.shPKM2 induced apoptosis and impaired autophagy in PANC-1 cells. Our results suggested that targeting PKM2 with an oncolytic adenovirus produced a strong antitumor effect, and that this strategy could broaden the therapeutic options for treating pancreatic cancer.
Highlights
The M2 isoform of pyruvate kinase (PKM2) is a key driver of glycolysis in cancer cells and has critical ‘non-metabolic’ functions in some cancers; the role of PKM2 in pancreatic cancer remains unclear
We further assessed the correlation between PKM2 expression and the clinical characteristics of pancreatic cancer patients (Table 1), and found that PKM2 expression was not related to gender or tumor stages but was significantly associated with age (P = 0.0020) and lymph node metastasis (P = 0.0436)
We found that PKM2 modulated cell proliferation and migration as well as tumor formation of pancreatic cancer
Summary
The M2 isoform of pyruvate kinase (PKM2) is a key driver of glycolysis in cancer cells and has critical ‘non-metabolic’ functions in some cancers; the role of PKM2 in pancreatic cancer remains unclear. The two splice variants of PKM pre-mRNA produce pyruvate kinase M1 (PKM1) and M2 (PKM2), which include exons 9 or 10, respectively.[5] An increasing number of studies have shown that PKM2 but not PKM1 is crucial for tumorigenic phenotype maintenance, cell cycle progression and tumor growth.[6,7] Recently, PKM2 was identified as a protein kinase and transcription factor coactivator in regulating brain tumorigenesis and colon cancer cell migration, respectively, which are divergent from its canonical role as a pyruvate kinase.[8,9] Modulating PKM2 in tumor angiogenesis was recently reported to be regulated by miR-148a and miR-152 expression.[10] PKM2 prevents apoptosis in hepatocellular carcinoma (HCC), and knockdown of PKM2 inhibited cell proliferation and induced apoptosis in HCC.[11] The outcome of patients with either HCC or pancreatic cancer is inversely correlated with PKM2 expression.[11,12,13]. Because of its multiple roles in tumorigenesis, PKM2 should be investigated as a target for pancreatic cancer therapy
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