Apolipoprotein E2 modulates cell cycle function to promote proliferation in pancreatic cancer cells via regulation of the c-Myc–p21Waf1signalling pathway

Abstract

Apolipoprotein E2 (ApoE2) is reportedly critical for cell proliferation and survival, and has been identified as a potential tumour-associated marker in many kinds of cancer. However, studies of the function and mechanisms of ApoE2 in pancreatic cancer proliferation and development are rare. In this study, we performed an analysis to determine the modulatory effects of ApoE2–LRP8 (lipoprotein receptor-related protein 8) pathway on cell cycle and cell proliferation, and explored its mechanisms in pancreatic cancer. High expression levels of ApoE2–LRP8/c-Myc were detected in tumour tissues and cell lines by immunohistochemistry and Western blotting. It was also shown that ApoE2–LRP8 induced phosphorylation of ERK1/2 to activate c-Myc and contribute to cell-cycle-related protein expression. ApoE2 conditions induced c-Myc binding to target gene sequences in the p21Waf1promoter, resulting in decreased transcription. ERK/c-Myc contributes to the promotion of the expression levels of cyclin D1, cdc2, and cyclin B1, and reduces p21Waf1activity, thereby promoting cell cycle distribution. We demonstrated the function of ApoE2–LRP8 in the activation of the ERK–c-Myc–p21Waf1signalling cascade and the modulation of G1/S and G2/M transition, indicating ApoE2–LRP8’s important role in the cancer cell proliferation. ApoE2 could serve as a diagnostic marker and chemotherapeutic target in pancreatic cancer.