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Hemagglutinin protease secreted by V. cholerae induced apoptosis in breast cancer cells by ROS mediated intrinsic pathway and regresses tumor growth in mice model

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Abstract

Conventional anticancer therapies are effective but have side effects, so alternative targets are being developed. Bacterial toxins that can kill cells or alter the cellular processes like proliferation, apoptosis and differentiation have been reported for cancer treatment. In this study we have shown antitumor activity of hemagglutinin protease (HAP) secreted by Vibrio cholerae. One µg of HAP showed potent antitumor activity when injected into Ehrlich ascites carcinoma (EAC) tumors in Swiss albino mice. Weekly administration of this dose is able to significantly diminish a large tumor volume within 3 weeks and increases the survival rates of cancerous mice. HAP showed apoptotic activity on EAC and other malignant cells. Increased level of pro-apoptotic p53 with increased ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2 signify that HAP induced apoptogenic signals lead to death of the tumor cells. In vivo and ex vivo studies suggest that mitochondrial dependent intrinsic pathway is responsible for this apoptosis. The level of ROS in malignant cells is reported to be higher than the normal healthy cells. HAP induces oxidative stress and increases the level of ROS in malignant cells which is significantly higher than the normal healthy cells. As a result the malignant cells cross the threshold level of ROS for cell survival faster than normal healthy cells. This mechanism causes HAP mediated apoptosis in malignant cells, but normal cells remain unaltered in the same environment. Our study suggests that HAP may be used as a new candidate drug for cancer therapy.

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Acknowledgment

We would like to thank Dr. Rathin Baral (CNCI, India) for providing EAC cells and Dr. Alok Sil (University of Calcutta, India) for using the bright field and fluorescence microscope. We are grateful to the central facility of FACS and the technical support of Mr. Somnath Chatterjee in confocal microscope of NICED, Kolkata. TR is supported by the post doctoral fellowship of Indian Council of Medical Research (ICMR PDF fellowship).

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  1. Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, 700010, India

    Tanusree Ray, Monoj Kumar Chakrabarti & Amit Pal

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  1. Tanusree Ray
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Ray, T., Chakrabarti, M.K. & Pal, A. Hemagglutinin protease secreted by V. cholerae induced apoptosis in breast cancer cells by ROS mediated intrinsic pathway and regresses tumor growth in mice model. Apoptosis 21, 143–154 (2016). https://doi.org/10.1007/s10495-015-1194-1

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