PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis. Therefore, it is important to fully understand the molecular mechanism underlying its occurrence and development. Pumilio RNA-binding family member 1 (PUM1) has been reported to function as an oncogene in ovarian cancer and nonsmall cell lung cancer. However, its role and mechanism in PDAC have not been fully illuminated. Here, we found that the PUM1 protein levels were higher in PDAC tissues than in adjacent tissues and that PUM1 levels were significantly associated with TNM stage and overall survival time, indicating a correlation between high PUM1 expression and poor prognosis in patients with PDAC. In vitro and in vivo assays showed that PUM1 knockdown inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), and promoted apoptosis in MIA PaCa-2 and PANC-1 cells. Through cDNA microarrays and ingenuity pathway analysis, we found that the activation of the eIF2 signaling pathway significantly correlated with PUM1 knockdown. These results were further confirmed by the increased levels of key components of the eIF2 signaling pathway, p-PERK, p-EIF2A, and ATF4 in PUM1 knockdown cells. We also found that PUM1 levels have a significant negative correlation with p-PERK levels in PDAC tissues and that PERK overexpression inhibited cell proliferation, migration, invasion, and EMT, and promoted apoptosis in vitro. Moreover, a PERK inhibitor alleviated the effects of PUM1 knockdown on cell proliferation, apoptosis, migration, invasion, and EMT. Taken together, our results revealed that PUM1 knockdown suppressed cell growth, invasion, and metastasis, and promoted apoptosis by activating the PERK/eIF2/ATF4 signaling pathway in PDAC cells. PUM1 could be a potential target to develop pharmaceuticals and novel therapeutic strategies for the treatment of PDAC.

ATF4 promotes lung cancer cell proliferation and invasion partially through regulating Wnt/β-catenin signaling

“…Some studies have indicated the promotion of cancer progression by ATF4 12 , 13 , 15 - 17 . In contrast, some studies have shown that ATF4 inhibits cancer progression 9 , 14 . Participation in the regulation of autophagy by ATF4 was reported 26 , and ATF4 also plays a role in sensitivity to chemotherapy 9 , 10 .…”

“…Zeng's study indicates that ATF4 promotes invasion and progression of breast carcinomas 12 , and Chen's experiments confirmed that ATF4 promotes proliferation and invasion of gliomas 13 . Others have provided evidence of its anti-cancer function 9 , 14 , and Dai proved that ATF4 inhibits the progression of pancreatic cancer 14 . ATF4 participates in the regulation of many molecular pathways.…”

“…Zeng proved that ATF4 contributes to the malignant features of breast cancer by regulating E-cadherin 12 . Other molecular links include PERK, MYC, and CCL2 14 - 16 . Some experiments show that ATF4 regulates Wnt/β-catenin signaling 11 , 17 .…”

NcPuf1 Is a Key Virulence Factor in Neospora caninum

“…While the PUM1 gene was silenced, the cell proliferation was significantly inhibited [39]. The deletion of PUM1 can decrease the proliferation of MIA, PaCa-2, and PANC-1 cells and promote their apoptosis [40]. Therefore, we speculate that the conserved function of the Puf protein is to promote proliferation.…”

Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

“…Several recent studies validate the role of the Pumilio family of RBPs in diverse biological processes in several organisms. Specific mRNA targets of two human Pumilio isoforms (PUM1 and PUM2) include oncogenes, tumor suppressors, and other factors implicated in oncogenic and cell death pathways [24][25][26] . In several organisms, PUM proteins also play a conserved role in stem cell proliferation and selfrenewal [27][28][29][30] .…”