Proanthocyanidin-Rich Fractions from Red Rice Extract Enhance TNF-α-Induced Cell Death and Suppress Invasion of Human Lung Adenocarcinoma Cell A549

Tumor necrosis factor-alpha (TNF-alpha) plays a key role in promoting tumor progression, such as stimulation of cell proliferation and metastasis via activation of NF-kappa B and AP-1. The proanthocyanidin-rich fraction obtained from red rice (PRFR) has been reported for its anti-tumor effects in cancer cells. This study investigated the molecular mechanisms associated with PRFR on cell survival and metastasis of TNF-alpha-induced A549 human lung adenocarcinoma. Notably, PRFR enhanced TNF-alpha-induced A549 cell death when compared with PRFP alone and caused a G0-G1 cell cycle arrest. Although, PRFR alone enhanced cell apoptosis, the combination treatment induced the cells that had been enhanced with PRFR and TNF-alpha to apoptosis that was less than PRFR alone and displayed a partial effect on caspase-8 activation and PARP cleavage. By using the autophagy inhibitor; 3-MA attenuated the effect of how PRFR enhanced TNF-alpha-induced cell death. This indicates that PRFR not only enhanced TNF-alpha-induced A549 cell death by apoptotic pathway, but also by induction autophagy. Moreover, PRFR also inhibited TNF-alpha-induced A549 cell invasion. This effect was associated with PRFR suppressed the TNF-alpha-induced level of expression for survival, proliferation, and invasive proteins. This was due to reduce of MAPKs, Akt, NF-kappa B, and AP-1 activation. Taken together, our results suggest that TNF-alpha-induced A549 cell survival and invasion are attenuated by PRFR through the suppression of the MAPKs, Akt, AP-1, and NF-kappa B signaling pathways.