Abstract
Curative management of pancreatic adenocarcinoma is limited because this malignancy remains resistant to most chemotherapeutic drugs. Strategies that reverse epigenetic alterations offer a unique opportunity for cancer cell reprogramming, which is valuable for development of new treatments. The aim of this work was to reprogram pancreatic ductal adenocarcinoma (PDAC) cells toward a less aggressive and drug-responsive phenotype. The process applied is called “epigenetic reprogramming”. To evaluate the efficiency of PDAC epigenetic reprogramming, we assessed tumor growth and drug response in PANC-1 cells after exposure to non-cytotoxic doses of the demethylating agent 5-azacytidine (5-AZA). Here, we showed that an epigenetic regimen using 5-AZA promoted an anti-cancer response by inhibiting PDAC tumor growth in vivo after the engraftment of treated cells. Remarkably, the subsequent addition of gemcitabine (GEM) to the 5-AZA-mediated reprogramming resulted in a marked growth inhibition effect in GEM-resistant pancreatic cancer cells. We observed that various characteristic peptides expressed in the pancreas, which included the antiproliferative hormone somatostatin (SST) and the SST receptor 2 (SSTR2), were significantly upregulated in the epigenetically reprogrammed PDAC cells. The inhibitory effect of octreotide (OCT), an SST analog, was tested on PDAC cells and found to be improved after cell reprogramming. Furthermore, we found that SST gene expression restoration following 5-AZA treatment or following knockdown of the DNA methyltransferase (DNMT) 1 enzyme was associated with the reversion of SST epigenetic silencing through regional CpG demethylation. Lastly, we confirmed the efficacy of 5-AZA-based epigenetic reprogramming in vivo using a PDAC tumor growth model. In conclusion, this study demonstrates that epigenetic reprogramming using the demethylating compound 5-AZA shows anti-cancer effects in PANC-1 cells and is potentially attractive for the treatment of solid tumors.
Highlights
Pancreatic cancer is one of the most aggressive and resistant forms of malignancy[1]
Tumor growth To investigate the prospective therapeutic use of epigenetic reprogramming in pancreatic adenocarcinoma, we first evaluated the effect of the demethylating agent 5-AZA on the four human pancreatic ductal adenocarcinoma (PDAC) cell lines PANC-1, Capan-2, PL45, and SU.[86-86]
Cell viability assays were performed and showed a clear dose–response effect, resulting in a gradual decrease in cell growth and significant toxicity after 3 days for the PDAC cells that had been treated with high doses of 5-AZA (Fig. 1)
Summary
Pancreatic cancer is one of the most aggressive and resistant forms of malignancy[1]. Represented by pancreatic ductal adenocarcinoma (PDAC), it represents the fifth leading cause of cancer-related death in industrialized countries[2]. Diagnosis is frequently late because of the absence of diseasespecific symptoms and new patients usually present with advanced or metastatic diseases. The deoxycytidine analog gemcitabine (GEM) and GEM-based combination therapies have been considered as standard treatments for limiting pancreatic cancer progression[3,4]. Tumor ablation remains the only potentially curative option for pancreatic cancer. Given that only 15–20% of PDAC patients are considered to be appropriate candidates for surgical resection and rapidly develop local recurrence[5], new therapeutic alternatives are urgently required
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