Abstract
Suberoylanilide hydroxamic acid (SAHA) represents one of the new class of anti-cancer drugs. However, multiple lines of clinical evidence indicate that SAHA might be sometimes ineffective on certain solid tumors including pancreatic cancer. In this study, we have found for the first time that RUNX2/mutant p53/TAp63-regulatory axis has a pivotal role in the determination of SAHA sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 cells. According to our present results, MiaPaCa-2 cells responded poorly to SAHA. Forced depletion of mutant p53 stimulated SAHA-mediated cell death of MiaPaCa-2 cells, which was accomapanied by a further accumulation of γH2AX and cleaved PARP. Under these experimental conditions, pro-oncogenic RUNX2 was strongly down-regulated in mutant p53-depleted MiaPaCa-2 cells. Surprisingly, RUNX2 silencing augmented SAHA-dependent cell death of MiaPaCa-2 cells and caused a significant reduction of mutant p53. Consistent with these observations, overexpression of RUNX2 in MiaPaCa-2 cells restored SAHA-mediated decrease in cell viability and increased the amount of mutant p53. Thus, it is suggestive that there exists a positive auto-regulatory loop between RUNX2 and mutant p53, which might amplify their pro-oncogenic signals. Intriguingly, knockdown of mutant p53 or RUNX2 potentiated SAHA-induced up-regulation of TAp63. Indeed, SAHA-stimulated cell death of MiaPaCa-2 cells was partially attenuated by p63 depletion. Collectively, our present observations strongly suggest that RUNX2/mutant p53/TAp63-regulatory axis is one of the key determinants of SAHA sensitivity of p53-mutated pancreatic cancer cells.
Highlights
The overall survival rate of the patients with various solid tumors has been clearly prolonged due to the improved therapy and surgical procedures
We have found for the first time that RUNX2 attenuates p53 family-dependent cell death following DNA damage, and RUNX2 gene silencing mediated by siRNA clearly enhances GEM sensitivity of pancreatic cancer cells irrespective of their p53 status [24,25,26,27]
We have focused on p53-mutated pancreatic cancer cells, and found that RUNX2/mutant p53/TAp63regulatory axis plays a pivotal role in the modulation of Suberoylanilide hydroxamic acid (SAHA)-mediated cell death
Summary
The overall survival rate of the patients with various solid tumors has been clearly prolonged due to the improved therapy and surgical procedures. Cancer remains the most lethal malignant tumor with an extremely poor prognosis (overall survival rate of around 7%) in spite of the extensive efforts [1,2,3,4]. Less than 10% of the patients with pancreatic cancer are diagnosed at an early stage due to the difficulty in its early detection, and most of the remaining patients do not have a chance to take a surgical resection attributed to its late stage. Majority of the patients who have received the surgery, suffer recurrence [5]. These advanced cases exhibit a severe resistance to the existing therapeutic modalities
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
