Autophagy Dependent Cell Death, Senescence and Differentiation by Abrus Agglutinin in Cancer Therapeutics

Abstract

Abrus agglutinin (AGG), a type II ribosome inactivating protein has been found to induce mitochondrial apoptosis. Initially, 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. Besides autophagy, we investigated mitophagy inducing potential of PUMA triggered by AGG in U87MG cells and established AGG induced ceramide as a chief mediator of mitophagy dependent cell death through activation of mitochondrial ROS and ER stress. Mechanistically, we identified a LC3 interacting region (LIR) at C-terminal end of PUMA which interacts with LC3 to induce mitophagy. Furthermore, we identified senescence inducing potential governed by AGG induced autophagy in prostate cancer cell line. Our study showed that accelerated expression of SIRT1 facilitated LAMP1 deacetylation in response to AGG insult and modulated autophagy. Likely, AGG induced colon CSC differentiation by increasing expression of BMP2. As per retrospective tumor specimen analysis, BMP2 expression was down regulated with colon cancer progression indicating its tumor suppressor function. Significant interaction of AGG induced BMP2 with hVps34 may be a breakthrough in autophagy machinery. The present study provided deep insight into the mechanism of AGG mediated tumor inhibition through activation of autophagy for the development of cancer therapeutics.