# Sestrin2 Knockdown Impairs Proliferation, Migration, Invasion, and Apoptosis in OSCC Cells via PI3K/AKT/mTOR and MAPK Pathways

## TL;DR

This study shows that reducing Sestrin2 in oral cancer cells slows growth and spread by affecting key signaling pathways.

## Contribution

The novel contribution is identifying Sestrin2 as an oncogene in OSCC through its regulation of PI3K/AKT/mTOR and MAPK pathways.

## Key findings

- Sestrin2 knockdown reduced cell proliferation, migration, and invasion in OSCC cells.
- Sestrin2 depletion induced apoptosis and altered BAX/BCL-2 levels in SAS cells.
- Sestrin2 silencing downregulated PI3K/AKT/mTOR and MAPK pathways in OSCC cells.

## Abstract

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with a poor prognosis. Sestrin2 (Sesn2), a stress-inducible protein, has been implicated in various cancers, but its precise role and mechanism in OSCC remain unclear. This study investigated the molecular mechanisms of Sesn2 in OSCC. Sesn2 expression was analyzed using data from TCGA and immunohistochemical results from the HPA. Functional assays, including CCK-8, flow cytometry for cell cycle, wound healing, and Transwell assays, were performed following Sesn2 knockdown with siRNA in OSCC cell lines (CAL-27 and SAS). Underlying mechanisms were investigated by Western blotting and ELISA for MMP-2 and MMP-9 levels. Sesn2 was significantly upregulated in OSCC tissues compared to normal controls. Its knockdown markedly suppressed cell proliferation, induced G1 phase cell cycle arrest, and impaired migratory and invasive capabilities. This reduction in invasion was further confirmed by decreased levels of MMP-2 and MMP-9 upon Sesn2 knockdown. Furthermore, Sesn2 silencing induced apoptosis via Caspase-3 activation with divergent BAX/BCL-2 modulation; SAS cells exhibited elevated BAX and reduced BCL-2, whereas these proteins remained unchanged in CAL-27 cells. Mechanistically, we found that Sesn2 depletion downregulated the PI3K/AKT/mTOR pathway and reduced the phosphorylation of AKT and p38 MAPK. Our findings demonstrate that Sesn2 functions as an oncogene in OSCC, promoting tumor progression by modulating the PI3K/AKT/mTOR and MAPK signaling pathways, suggesting its potential as a therapeutic target for OSCC.