Apolipoprotein E2 modulates cell cycle function to promote proliferation in pancreatic cancer cells via regulation of the c-Myc–p21^Waf1signalling 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 p21Waf1 promoter, resulting in decreased transcription. ERK/c-Myc contributes to the promotion of the expression levels of cyclin D1, cdc2, and cyclin B1, and reduces p21Waf1 activity, thereby promoting cell cycle distribution. We demonstrated the function of ApoE2–LRP8 in the activation of the ERK–c-Myc–p21Waf1 signalling 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.

miR-362-3p suppresses ovarian cancer by inhibiting LRP8

“…Furthermore, LRP8 was repressed by miR-1262, and overexpression of LRP8 obviously elevated cell growth and tumor progression in breast cancer [14] . In contrast, LRP8 is downstream of apolipoprotein E2, which promotes cell growth and reduces cell apoptosis by activating the phosphorylation of extracellular signal‐regulated kinase (ERK)−1/2 signaling in pancreatic cancer cells [27] . Unfortunately, the biological role of LRP8 in ovarian cancer development remains unclear.…”

Apolipoprotein E2 Promotes the Migration and Invasion of Pancreatic Cancer Cells via Activation of the ERK1/2 Signaling Pathway

“…13 Additionally, we found that ApoE2 was overexpressed in pancreatic cancer tissues, and further results indicated that ApoE2 was essential for cell proliferation and cell cycle progression in pancreatic cancer cells. 14 In this study, we explored the role of ApoE2 in pancreatic cancer migration and invasion and the underlying mechanism. We found that ApoE2 overexpression induced significant enhancements in the cell migration and invasion capacities of pancreatic cancer cells and accelerated the EMT process.…”

“…[15][16][17] Our previous study demonstrated that ApoE2 could activate ERK1/2 signaling in pancreatic cancer cells. 14 In the present study, we explored whether the AKT, ERK1/2 and JNK signaling pathways were involved in the ApoE2-mediated promotion of the cell migration and invasion of PANC-1 cells. We found that of the three kinases mentioned above, the level of phosphorylated ERK1/2 was significantly increased in a time-dependent manner after treatment of the cells with rhApoE2 ( Figure 5A).…”

“…13 Our previous study showed that the expression of ApoE2 in pancreatic cancer tissues is higher than that in adjacent normal tissues, induces cell proliferation and enhances G1/S and G2/M transition. 14 Accumulating evidence has indicated that ApoE modulates the AKT, ERK1/2, and JNK signaling pathways in various processes, including cell metabolism, cell survival and hippocampal synaptic function. [15][16][17] The MAPK/ ERK1/2 signaling pathway is an important intracellular pathway that regulates multiple cellular biological responses, such as cell growth, apoptosis, migration and invasion.…”

“…21 In our previous study, we demonstrated that ApoE2 promoted the phosphorylation of ERK1/2 by binding to the LRP-8 receptor in PDAC. 14 Consequently, we hypothesized that ApoE2 might play a role in modulating PDAC cell migration and invasion by activating ERK1/2 signaling.…”