Abrus agglutinin promotes irreparable DNA damage by triggering ROS generation followed by ATM-p73 mediated apoptosis in oral squamous cell carcinoma.

Abstract

Oral cancer, a type of head and neck cancer, is ranked as one of the top most malignancies in India. Herein, we evaluated the anticancer efficacy of Abrus agglutinin (AGG), a plant lectin, in oral squamous cell carcinoma. AGG selectively inhibited cell growth, and caused cell cycle arrest and mitochondrial apoptosis through a reactive oxygen species (ROS)-mediated ATM-p73 dependent pathway in FaDu cells. AGG-induced ROS accumulation was identified as the major mechanism regulating apoptosis, DNA damage and DNA-damage response, which were significantly reversed by ROS scavenger N-acetylcysteine (NAC). Moreover, AGG was found to interact with mitochondrial manganese-dependent superoxide dismutase that might inhibit its activity and increase ROS in FaDu cells. In oral cancer p53 is mutated, thus we focused on p73; AGG resulted in p73 upregulation and knock down of p73 caused a decrease in AGG-induced apoptosis. Interestingly, AGG-dependent p73 expression was found to be regulated by ROS, which was reversed by NAC treatment. A reduction in the level of p73 in AGG-treated shATM cells was found to be associated with a decreased apoptosis. Moreover, administration of AGG (50 μg/kg body weight) significantly inhibited the growth of FaDu xenografts in athymic nude mice. In immunohistochemical analysis, the xenografts from AGG-treated mice displayed a decrease in PCNA expression and an increase in caspase-3 activation as compared to the controls. In conclusion, we established a connection among ROS, ATM and p73 in AGG-induced apoptosis, which might be useful in enhancing the therapeutic targeting of p53 deficient oral squamous cell carcinoma.

• Authors: Niharika Sinha, Prashanta K Panda, Prajna P Naik, Durgesh N Das, Subhadip Mukhopadhyay, Tapas K Maiti, Muthu K Shanmugam, Arunachalam Chinnathambi, M E Zayed, Sulaiman A Alharbi, Gautam Sethi, Rajesh Agarwal, Sujit K Bhutia
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 56 Issue 11 Pg. 2400-2413 (Nov 2017) ISSN: 1098-2744 [Electronic] United States
• PMID: 28543759 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• Plant Lectins
• Reactive Oxygen Species
• Tumor Protein p73
• abrus agglutinin
• Ataxia Telangiectasia Mutated Proteins

Topics

• Abrus (chemistry)
• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Damage (drug effects)
• Humans
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism, pathology)
• Models, Molecular
• Mouth (drug effects, metabolism, pathology)
• Mouth Neoplasms (drug therapy, metabolism, pathology)
• Plant Lectins (chemistry, pharmacology, therapeutic use)
• Reactive Oxygen Species (metabolism)
• Tumor Protein p73 (metabolism)