pitavastatin and Mouth-Neoplasms

Despite increasing knowledge on oral and esophageal squamous cell carcinoma (OSCC and ESCC), specific medicines against both have not yet been developed. Here, we aimed to find novel anticancer drugs through functional cell-based screening of an FDA-approved drug library against OSCC and ESCC. Pitavastatin, an HMGCR inhibitor, emerged as an anticancer drug that inhibits tumor growth by downregulating AKT and ERK signals in OSCC and ESCC cells. One of the mechanisms by which pitavastatin inhibits cell growth might be the suppression of MET signaling through immature MET due to dysfunction of the Golgi apparatus. Moreover, the sensitivity of tumor growth to pitavastatin might be correlated with

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Cell Proliferation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Mice; Mouth Neoplasms; Proto-Oncogene Proteins c-met; Quinolines; Random Allocation; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Triazines; Xenograft Model Antitumor Assays

Statins are a class of lipid-lowering drugs that have recently been used in drug repositioning in the treatment of human cancer. However, the underlying mechanism of statin-induced cancer cell death has not been clearly defined. In the present study, we evaluated the anticancer effect of pitavastatin on oral squamous cell carcinoma (OSCC), SCC15 and SCC4 cells and found that FOXO3a might be a direct target in pitavastatin-induced cancer cell death. Our data revealed that pitavastatin selectively suppressed cell viability and induced intrinsic apoptosis in a FOXO3a-dependent manner in SCC15 cells while no effect was observed in SCC4 cells. Notably, treatment with pitavastatin in SCC15 cells induced the nuclear translocation of FOXO3a via dual regulation of two upstream kinases, AMPK and Akt, resulting in the up-regulation of PUMA, a transcriptional target gene of FOXO3a. Furthermore, our data revealed that FOXO3a-mediated PUMA induction plays a role in pitavastatin-induced intrinsic apoptosis in SCC15 cells. Taken together, our findings suggest that pitavastatin activates the FOXO3a/PUMA apoptotic axis by regulation of nuclear translocation of FOXO3a via Akt/FOXO3a or AMPK/FOXO3a signalling. Therefore, these findings might help to elucidate the underlying mechanism of the anticancer effects of pitavastatin on OSCC.

Topics: Adenylate Kinase; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Forkhead Box Protein O3; Humans; Models, Biological; Mouth Neoplasms; Neoplasm Metastasis; Phosphorylation; Protein Transport; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Quinolines; Signal Transduction