Prostaglandin 15d-PGJ inhibits proliferation of lung adenocarcinoma cells by inducing ROS production and activation of apoptosis via sirtuin-1.

Lung adenocarcinoma (LUADC) belongs to the most prevalent and lethal cancer types. As 15-deoxy-Δ12,14-prostaglandin J (15d-PGJ) displays anti-oxidative, -inflammatory, and -cancer properties, we investigated whether this cyclopentenone PG, a stable degradation end-product of cyclooxygenase-generated PGD, exerts beneficial effects in three LUADC cell lines (A549, H1299, H23). We here report that 15d-PGJ had substantial cytotoxic effects in all three LUADC cell lines by promoting early apoptosis and inhibiting the cell cycle, proliferation, and migration. As indicators of cell malignancy, scratch closure and colony formation were significantly inhibited by 15d-PGJ. 15d-PGJ induced generation of ROS and subsequent activation of MAPKs. Expression of Nrf-2, a well-known tumor driver, was markedly diminished by 15d-PGJ treatment. Although PPARγ, DP1, and DP2 are expressed in LUADC cells, blocking these receptors with specific inhibitors (SR16832 and BW245C) did not reverse 15d-PGJ-mediated cytotoxicity, suggesting receptor-independent effects. 15d-PGJ decreased SIRT1 expression in LUADC cells and the knockdown of SIRT1 diminished the cytotoxic effects of 15d-PGJ. Importantly, 15d-PGJ significantly reduced tumor growth using the chorioallantoic membrane (CAM) assay. The structural analog of 15d- PGJ, 9,10-dihydro-15d-PGJ (lacking the α,β-unsaturated ketone structural element), did not show any toxic effects in LUADC cells. Altogether, our findings suggest that 15d-PGJ led to significantly reduced tumor growth and cell proliferation in three LUADC cell lines. The CAM assay results suggest that 15d-PGJ is a suitable endogenous compound to interfere with LUADC tumor progression. We show that SIRT1 modulates the effects of 15d-PGJ and may be used as a therapeutic target for LUADC.