Pitavastatin induces apoptosis in oral squamous cell carcinoma through activation of FOXO3a
Naeun Lee1, Nirmala Tilija Pun1, Won-Jun Jang1
1College of Pharmacy, Keimyung University, Daegu, South Korea.
Abstract:
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.
Insights
Pitavastatin, a statin drug, shows anticancer effects on oral cancer cells by inducing cell death. It activates the FOXO3a/PUMA pathway, a key mechanism in cancer cell apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Statins are lipid-lowering drugs with potential for cancer treatment through drug repositioning.
- The precise mechanisms of statin-induced cancer cell death remain unclear.
- Oral squamous cell carcinoma (OSCC) is a significant global health concern.
Purpose of the Study:
- To investigate the anticancer effects of pitavastatin on OSCC cell lines.
- To elucidate the molecular mechanisms underlying pitavastatin-induced cancer cell death.
- To identify potential molecular targets involved in pitavastatin's anti-OSCC activity.
Main Methods:
- Utilized SCC15 and SCC4 human OSCC cell lines.
- Assessed the impact of pitavastatin on cell viability and apoptosis.
- Investigated the role of FOXO3a, AMPK, Akt, and PUMA in pitavastatin's mechanism of action.
- Examined the nuclear translocation of FOXO3a.
Main Results:
- Pitavastatin selectively suppressed SCC15 cell viability and induced apoptosis in a FOXO3a-dependent manner.
- Pitavastatin treatment led to nuclear translocation of FOXO3a in SCC15 cells.
- This translocation was regulated by AMPK and Akt kinases.
- FOXO3a activation resulted in increased PUMA expression, contributing to apoptosis.
Conclusions:
- Pitavastatin demonstrates selective anticancer effects against OSCC cells.
- The FOXO3a/PUMA apoptotic axis is a key mediator of pitavastatin's anti-cancer activity.
- Pitavastatin's mechanism involves regulating FOXO3a nuclear translocation via Akt/FOXO3a or AMPK/FOXO3a signaling pathways.
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