Depletion of pro-oncogenic RUNX2 enhances gemcitabine (GEM) sensitivity of p53-mutated pancreatic cancer Panc-1 cells through the induction of pro-apoptotic TAp63
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Toshinori Ozaki1, Mizuyo Nakamura1, Takehiro Ogata1, Meijie Sang1,2, Hiroyuki Yoda3, Kiriko Hiraoka3, Meixiang Sang1,4, Osamu Shimozato1
1Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan
2Department of Regenerative Medicine, Graduate School of Medicine and Pharmatheutical Science, University of Toyama, Toyama, Japan
3Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan
4Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
Toshinori Ozaki, email: firstname.lastname@example.org
Keywords: gemcitabine, mutant p53, pancreatic cancer, RUNX2, TAp63
Received: February 16, 2016 Accepted: September 25, 2016 Published: October 04, 2016
Recently, we have described that siRNA-mediated silencing of runt-related transcription factor 2 (RUNX2) improves anti-cancer drug gemcitabine (GEM) sensitivity of p53-deficient human pancreatic cancer AsPC-1 cells through the augmentation of p53 family TAp63-dependent cell death pathway. In this manuscript, we have extended our study to p53-mutated human pancreatic cancer Panc-1 cells. According to our present results, knockdown of mutant p53 alone had a marginal effect on GEM-mediated cell death of Panc-1 cells. We then sought to deplete RUNX2 using siRNA in Panc-1 cells and examined its effect on GEM sensitivity. Under our experimental conditions, RUNX2 knockdown caused a significant enhancement of GEM sensitivity of Panc-1 cells. Notably, GEM-mediated induction of TAp63 but not of TAp73 was further stimulated in RUNX2-depleted Panc-1 cells, indicating that, like AsPC-1 cells, TAp63 might play a pivotal role in the regulation of GEM sensitivity of Panc-1 cells. Consistent with this notion, forced expression of TAp63α in Panc-1 cells promoted cell cycle arrest and/or cell death, and massively increased luciferase activities driven by TAp63-target gene promoters such as p21WAF1 and NOXA. In addition, immunoprecipitation experiments indicated that RUNX2 forms a complex with TAp63 in Panc-1 cells. Taken together, our current observations strongly suggest that depletion of RUNX2 enhances the cytotoxic effect of GEM on p53-mutated Panc-1 cells through the stimulation of TAp63-dependent cell death pathway even in the presence of a large amount of pro-oncogenic mutant p53, and might provide an attractive strategy to treat pancreatic cancer patients with p53 mutations.
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