Antitumor activity of Abrus agglutinin through activation of apoptosis and autophagy-dependent cell death

Abstract

Abrus agglutinin (AGG), isolated from Abrus precatorious, a medicinal plant induces antitumor activity through activation of apoptosis and autophagy-dependent cell death. AGG effectively inhibited the cell viability of different oral squamous cell carcinoma with IC50 value 1-10 µg/ml. AGG selectively inhibited growth and, caused cell cycle arrest and mitochondrial apoptosis through reactive oxygen species (ROS) mediated ATM-p73 dependent pathway in FaDu cells. AGG-induced ROS accumulation was identified as chief mechanism of its effect on apoptosis, DNA damage and DNA-damage response which significantly reversed by ROS scavenger N-acetylcysteine (NAC). Moreover, AGG found to interact with mitochondrial manganese-dependent superoxide dismutase which might inhibit its activity and upshot ROS in FaDu cells. Moreover, we documented that AGG mediated Akt dephosphorylation led to ER stress resulting in the induction of autophagy-dependent cell death through the canonical pathway in cervical cancer cells. At the molecular level, AGG induced ER stress in PERK dependent pathway and inhibition of ER stress by salubrinal, eIF2α phosphatase inhibitor as well as siPERK reduced autophagic death in the presence of AGG. Further, our in silico and colocalization study showed that AGG interacted with pleckstrin homology (PH) domain of Akt to suppress its phosphorylation and consequent downstream mTOR dephosphorylation in HeLa cells. Moreover, administration of AGG (50 μg/kg body weight) significantly inhibited the growth of FaDu xenografts in athymic nude mice. In conclusion, we established that AGG-stimulated cell death by apoptosis and autophagy might be used as a novel tumor suppressor mechanism for cancer therapy.