Inhibition of TRIM32 by ibr-7 treatment sensitizes pancreatic cancer cells to gemcitabine via mTOR/p70S6K pathway.

Abstract

Pancreatic cancer is one of the most notorious diseases for being asymptomatic at early stage and high mortality rate thereafter. However, either chemotherapy or targeted therapy has rarely achieved success in recent clinical trials for pancreatic cancer. Novel therapeutic regimens or agents are urgently in need. Ibr-7 is a novel derivative of ibrutinib, displaying superior antitumour activity in pancreatic cancer cells than ibrutinib. In vitro studies showed that ibr-7 greatly inhibited the proliferation of BxPC-3, SW1990, CFPAC-1 and AsPC-1 cells via the induction of mitochondrial-mediated apoptosis and substantial suppression of mTOR/p70S6K pathway. Moreover, ibr-7 was able to sensitize pancreatic cancer cells to gemcitabine through the efficient repression of TRIM32, which was positively correlated with the proliferation and invasiveness of pancreatic cancer cells. Additionally, knockdown of TRIM32 diminished mTOR/p70S6K activity in pancreatic cancer cells, indicating a positive feedback loop between TRIM32 and mTOR/p70S6K pathway. To conclude, this work preliminarily explored the role of TRIM32 in the malignant properties of pancreatic cancer cells and evaluated the possibility of targeting TRIM32 to enhance effectiveness of gemcitabine, thereby providing a novel therapeutic target for pancreatic cancer.

• Authors: Bo Zhang, You-You Yan, Yang-Qin Gu, Fei Teng, Xu Lin, Xing-Lu Zhou, Jin-Xin Che, Xiao-Wu Dong, Li-Xin Zhou, Neng-Ming Lin
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 26 Issue 2 Pg. 515-526 (01 2022) ISSN: 1582-4934 [Electronic] England
• PMID: 34921503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Transcription Factors
• Tripartite Motif Proteins
• Deoxycytidine
• TRIM32 protein, human
• Ubiquitin-Protein Ligases
• MTOR protein, human
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Gemcitabine

Topics

• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Deoxycytidine (analogs & derivatives)
• Humans
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (genetics)
• TOR Serine-Threonine Kinases (metabolism)
• Transcription Factors
• Tripartite Motif Proteins (genetics)
• Ubiquitin-Protein Ligases (genetics)
• Gemcitabine