Co-expression of FOXL1 and PP2A inhibits proliferation inducing apoptosis in pancreatic cancer cells via promoting TRAIL and reducing phosphorylated MYC

Abstract

Abstract. Pancreatic cancer is usually diagnosed in the advanced stages and is sensitive to only few therapies. The forkhead box L1 (FOXL1) and protein phosphatase 2A (PP2A) have been recognized to be tumor suppressive in human pancreatic cancers. In the present study, we co-expressed the two tumor suppressive molecules with a '2A peptide' linker, which guaranteed the two molecules were transcribed into one mRNA, whereas they were translated into two separate proteins, in pancreatic cancer Panc-1 cells, and investigated the inhibition of the two molecules on the proliferation and migration of Panc-1 cells. Results demonstrated that, either overexpression of FOXL1 or PP2A via adenovirus significantly inhibited the proliferation of Panc-1 cells, whereas promoted apoptosis in such cells. Moreover, the co-expression of both FOXL1 and PP2A exerted synergistic antitumor effect in Panc-1 cells, with significantly higher proliferation inhibition and tumor induction. In addition, we found that the overexpressed FOXL1 promoted the TNF-related apoptosis-inducing ligand (TRAIL), whereas the overexpressed PP2A downregulated the phosphorylation of c-MYC. The co-expression of FOXL1 and PP2A presented both functions in Panc-1 cells. In conclusion, the adenovirus-mediated co-expression of FOXL1 and PP2A with the 2A peptide linker exterts synergistic suppression of pancreatic cancer cells via inhibiting the growth and promoting apoptosis of cancer cells, probably via upregulating TRAIL and reducing the phosphorylation of MYC.

Strategies to target the cancer driver MYC in tumor cells

“…A previous study showed that the expression of a MYC antisense RNA from an adenovirus can induce apoptosis of gastric cancer cells ( 151 ). An adenoviral vector has been also used for the coexpression of tumor suppressor genes in pancreatic cancer cells leading to proliferation inhibition and reduced MYC phosphorylation ( 152 ). Like adenovirus, adeno-associated virus (AAV) is non-enveloped but smaller in size (approximately 25 nm) and has a 5-kbp genome.…”