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.

中文翻译：

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匹伐他汀通过激活FOXO3a诱导口腔鳞状细胞癌细胞凋亡。

他汀类药物是一类降脂药物，最近已用于药物重新定位以治疗人类癌症。然而，他汀类药物诱导的癌细胞死亡的潜在机制尚未明确。在本研究中，我们评估了匹伐他汀对口腔鳞状细胞癌（OSCC），SCC15和SCC4细胞的抗癌作用，并发现FOXO3a可能是匹伐他汀诱导的癌细胞死亡的直接靶标。我们的数据显示匹伐他汀在SCC15细胞中以FOXO3a依赖性方式选择性抑制细胞活力并诱导内在凋亡，而在SCC4细胞中未观察到作用。值得注意的是，在两个SCC15细胞中用匹伐他汀进行治疗可通过双重调节两种上游激酶AMPK和Akt诱导FOXO3a的核易位，从而导致PUMA的上调，FOXO3a的转录靶基因。此外，我们的数据显示FOXO3a介导的PUMA诱导在匹伐他汀诱导的SCC15细胞内在凋亡中起作用。两者合计，我们的发现表明匹伐他汀通过Akt / FOXO3a或AMPK / FOXO3a信号传导调节FOXO3a的核易位，从而激活FOXO3a / PUMA的凋亡轴。因此，这些发现可能有助于阐明匹伐他汀对OSCC的抗癌作用的潜在机制。