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Int J Biol Macromol. 2019 Nov 9. pii: S0141-8130(19)35707-1. doi: 10.1016/j.ijbiomac.2019.11.079. [Epub ahead of print]

Abrus agglutinin inhibits oral carcinogenesis through inactivation of NRF2 signaling pathway.

Author information

1
Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundargarh, Odisha, India.
2
Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India.
3
Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Saudi Arabia.
4
Department of Biotechnology, Indian Institute of Technology, Kharagpur, India.
5
Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundargarh, Odisha, India. Electronic address: sujitb@nitrkl.ac.in.

Abstract

Abrus agglutinin (AGG), a heterotetrameric type II ribosome inactivating protein isolated from the seeds of Abrus precatorius shows potent antitumor activity in different cancer models. We examined the role of antioxidant system in modulation of the anticancer activity of AGG in in vitro and in hamster model of oral cancer. AGG promotes apoptosis through accumulation of ROS in CAL33 cells. Interestingly, our data showed that AGG decreases the activity of antioxidant enzymes including superoxide dismutase, catalase, glutathione peroxidase in CAL33 cells indicating antioxidant enzyme inhibition leads to AGG-induced ROS accumulation. Moreover, AGG inhibits expression of NRF2, transcription factor which regulates the expression of antioxidant enzymes in CAL33 cells. We found that AGG induces autophagy stimulation and loss of p62 expression in CAL33 cells. Furthermore, it showed that NRF2 expression is restored in the presence of 3-methyladenine and Baficomycin-A1 establishing role of autophagy in modulation of NRF2 through p62. Our study showed that AGG significantly inhibited tumor growth in DMBA-induced carcinogenesis. In immunohistochemical analysis, AGG-treated tumor displays higher caspase 3 expression and less p62 and NRF2 expression in comparison to the control. In conclusion, AGG-induced degradation of NRF2 through autophagy leads to ROS accumulation dependent apoptosis which might be used for treatment of oral cancer.

KEYWORDS:

Abrus agglutinin; Apoptosis; Autophagy; NRF2; Oral cancer; Reactive oxygen species

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