Journal
JOURNAL OF CANCER
Volume 12, Issue 5, Pages 1406-1420Publisher
IVYSPRING INT PUBL
DOI: 10.7150/jca.47032
Keywords
COL11A1; Akt; GEM; apoptosis; chemoresistance
Categories
Funding
- National Natural Fund [31370861]
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COL11A1 modulates apoptotic inhibition and chemoresistance in pancreatic cancer cells by activating the Akt/CREB/BCL-2/BAX signaling pathway, suggesting it may serve as a distinct prognostic indicator and an attractive therapeutic target for PDAC.
Collagen XI, a member of the collagen family, is present in the extracellular matrix (ECM), and high collagen XI/aI (COL11A1) expression in tumor tissue is reportedly correlated with the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC). However, the function of COL11A1 in the development of pancreatic cancer cells remains unclear. In the current study, we assessed mRNA expression of COL11A1 and its receptors and created a testing-model of both a COL11A1-overexpressing tumor microenvironment and/or altered-COL11A1 expression in pancreatic cancer cell lines. Next, we investigated the mechanism by which COL11A1 affects growth, gemcitabine (GEM) resistance and apoptosis in pancreatic cancer cells. We demonstrated that COL11A1 phosphorylated Akt(Ser473), promoting proliferation of cancer cells and inhibiting their apoptosis. Additionally, our data showed that COL11A1/Akt/CREB altered the balance between BCL-2 and BAX and mediated their mitochondrial translocation in pancreatic cancer cells. The COL11A1/Akt axis induced disruption of mitochondrial transmembrane function, enabling mitochondria-mediated apoptotic evasion to promote chemoresistance. We also explored the regulatory effect of COL11A1/Akt on molecular signaling in the mitochondria-mediated apoptotic program. COL11A1/Akt disturbed the BCL-2/BAX balance, inhibiting cytochrome c (Cyt-C) release and binding of Apaf-1/procaspase-9/Cyt-C, which suppressed the apoptotic program and induced GEM resistance in pancreatic cancer cells. In conclusion, COL11A1 modulates apoptotic inhibition and chemoresistance in pancreatic cancer cells by activating the Akt/CREB/BCL-2/BAX signaling pathway. COL11A1 may represent a distinct prognostic indicator and may be an attractive therapeutic target for PDAC.
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