Glycogen synthase kinase-3β participates in acquired resistance to gemcitabine in pancreatic cancer.

Abstract

Acquisition of resistance to gemcitabine is a challenging clinical and biological hallmark property of refractory pancreatic cancer. Here, we investigated whether glycogen synthase kinase (GSK)-3β, an emerging therapeutic target in various cancer types, is mechanistically involved in acquired resistance to gemcitabine in human pancreatic cancer. This study included 3 gemcitabine-sensitive BxPC-3 cell-derived clones (BxG30, BxG140, BxG400) that acquired stepwise resistance to gemcitabine and overexpressed ribonucleotide reductase (RR)M1. Treatment with GSK3β-specific inhibitor alone attenuated the viability and proliferation of the gemcitabine-resistant clones, while synergistically enhancing the efficacy of gemcitabine against these clones and their xenograft tumors in rodents. The gemcitabine-resensitizing effect of GSK3β inhibition was associated with decreased expression of RRM1, reduced phosphorylation of Rb protein, and restored binding of Rb to the E2 transcription factor (E2F)1. This was followed by decreased E2F1 transcriptional activity, which ultimately suppressed the expression of E2F1 transcriptional targets including RRM1, CCND1 encoding cyclin D1, thymidylate synthase, and thymidine kinase 1. These results suggested that GSK3β participates in the acquisition of gemcitabine resistance by pancreatic cancer cells via impairment of the functional interaction between Rb tumor suppressor protein and E2F1 pro-oncogenic transcription factor, thereby highlighting GSK3β as a promising target in refractory pancreatic cancer. By providing insight into the molecular mechanism of gemcitabine resistance, this study identified a potentially novel strategy for pancreatic cancer chemotherapy.

• Authors: Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Dilireba Bolidong, Osamu Takeuchi, Tomoharu Miyashita, Toshinari Minamoto
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 12 Pg. 4405-4416 (Dec 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32986894 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antimetabolites, Antineoplastic
• E2F1 Transcription Factor
• Retinoblastoma Protein
• Deoxycytidine
• Cyclin D1
• RRM1 protein, human
• Ribonucleoside Diphosphate Reductase
• Thymidylate Synthase
• Thymidine Kinase
• thymidine kinase 1
• Glycogen Synthase Kinase 3 beta
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin D1 (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm
• E2F1 Transcription Factor (metabolism)
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, physiology)
• Heterografts
• Humans
• Mice
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, metabolism)
• Phosphorylation
• Retinoblastoma Protein (metabolism)
• Ribonucleoside Diphosphate Reductase (metabolism)
• Thymidine Kinase (metabolism)
• Thymidylate Synthase (metabolism)
• Transcription, Genetic
• Gemcitabine