Abrus Agglutinin, a type II ribosome inactivating protein inhibits Akt/PH domain to induce endoplasmic reticulum stress mediated autophagy-dependent cell death

Panda, Prashanta Kumar and Behera, Birendra and Meher, Biswa Ranjan and Das, Durgesh Nandini and Mukhopadhyay, Subhadip and Sinha, Niharika and Naik, Prajna Paramita and Roy, Bibhas and Das, Joyjyoti and Paul, Subhankar and Maiti, Tapas K and Agarwal, Rajesh and Bhutia, Sujit K (2017) Abrus Agglutinin, a type II ribosome inactivating protein inhibits Akt/PH domain to induce endoplasmic reticulum stress mediated autophagy-dependent cell death. In: MOLECULAR CARCINOGENESIS, 56 (2). pp. 389-401.

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Abstract

Abrus agglutinin (AGG), a type II ribosome-inactivating protein has been found to induce mitochondrial apoptosis. In the present study, we documented that AGG-mediated Akt dephosphorylation led to ER stress resulting the induction of autophagy-dependent cell death through the canonical pathway in cervical cancer cells. Inhibition of autophagic death with 3-methyladenine (3-MA) and siRNA of Beclin-1 and ATG5 increased AGG-induced apoptosis. Further, inhibiting apoptosis by Z-DEVD-FMK and N-acetyl cysteine (NAC) increased autophagic cell death after AGG treatment, suggesting that AGG simultaneously induced autophagic and apoptotic death in HeLa cells. Additionally, it observed that AGG-induced autophagic cell death in Bax knock down (Bax-KD) and 5-FU resistant HeLa cells, confirming as an alternate cell killing pathway to apoptosis. At the molecular level, AGG-induced ER stress in PERK dependent pathway and inhibition of ER stress by salubrinal, eIF2 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. We showed that Akt overexpression could not augment GRP78 expression and reduced autophagic cell death by AGG as compared to pcDNA control, indicating Akt modulation was the upstream signal during AGG's ER stress mediated autophagic cell death. In conclusion, we established that AGG stimulated cell death by autophagy might be used as an alternative tumor suppressor mechanism in human cervical cancer. (c) 2016 Wiley Periodicals, Inc.

Item Type:	Journal Article
Publication:	MOLECULAR CARCINOGENESIS
Publisher:	WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Additional Information:	Copy right for this article belongs to the WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	09 Mar 2017 04:45
Last Modified:	25 Feb 2019 12:12
URI:	http://eprints.iisc.ac.in/id/eprint/56326

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