Depletion of pro-oncogenic RUNX2 enhances gemcitabine (GEM) sensitivity of p53-mutated pancreatic cancer Panc-1 cells through the induction of pro-apoptotic TAp63
| Autor: | Kiriko Hiraoka, Meijie Sang, Osamu Shimozato, Takehiro Ogata, Mizuyo Nakamura, Hiroyuki Yoda, Meixiang Sang, Toshinori Ozaki |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death Antimetabolites Antineoplastic Cell cycle checkpoint endocrine system diseases RUNX2 pancreatic cancer Apoptosis Core Binding Factor Alpha 1 Subunit Deoxycytidine 03 medical and health sciences 0302 clinical medicine Pancreatic cancer Cell Line Tumor Medicine Cytotoxic T cell Humans TAp63 Gene knockdown business.industry mutant p53 gemcitabine Cancer Membrane Proteins Cell Cycle Checkpoints medicine.disease Genes p53 Gemcitabine Pancreatic Neoplasms 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology Mutation Cancer research business medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Toshinori Ozaki 1 , Mizuyo Nakamura 1 , Takehiro Ogata 1 , Meijie Sang 1, 2 , Hiroyuki Yoda 3 , Kiriko Hiraoka 3 , Meixiang Sang 1, 4 , Osamu Shimozato 1 1 Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba, Japan 2 Department of Regenerative Medicine, Graduate School of Medicine and Pharmatheutical Science, University of Toyama, Toyama, Japan 3 Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba, Japan 4 Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China Correspondence to: Toshinori Ozaki, email: tozaki@chiba-cc.jp Keywords: gemcitabine, mutant p53, pancreatic cancer, RUNX2, TAp63 Received: February 16, 2016 Accepted: September 25, 2016 Published: October 04, 2016 ABSTRACT 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 p21 WAF1 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. |
| Databáze: | OpenAIRE |
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