Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential
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Rekha Khandia1,6, Bramhadev Pattnaik2, Katherukamem Rajukumar1, Atul Pateriya1, Sandeep Bhatia1, Harshad Murugkar1, Anil Prakash3, Hare Krishna Pradhan4, Kuldeep Dhama5, Ashok Munjal6, Sunil K. Joshi7
1ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
2Project Directorate on Foot and Mouth Disease, Mukteswar, Uttarakhand, India
3Department of Microbiology, Barkatullah University, Bhopal, Madhya Pradesh, India
4Ex-Avian Influenza National Consultant, Indian Office of WHO Consultant, Bhartiya Kala Kendra, New Delhi, India
5Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly Uttar Pradesh, India
6Department of Biochemistry and Genetics, Barkatullah University, Bhopal, Madhya Pradesh, India
7Cellular Immunology Laboratory, Frank Reidy Research Center of Bioelectrics, College of Health Sciences, Old Dominion University, Norfolk, VA USA
Sunil K. Joshi, email: [email protected]
Ashok Munjal, email: [email protected]
Keywords: anthrax toxin receptor, bacillus anthracis, c-Met receptor, lethal factor, protective antigen
Received: January 02, 2017 Accepted: March 07, 2017 Published: March 15, 2017
Bacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p < 0.01) reduction in proliferation of tumor cells with mean inhibition indices of 28.0 ± 1.37% and 19.6 ± 1.47% respectively. However, treatment with rPA alone had no significant anti-proliferative effect as evident by low mean inhibition index of 3.4 ± 3.87%. The higher inhibition index observed for rLF alone as compared to LeTx is contrary to the existing knowledge on LF, which explains the requirement of PA dependent endocytosis for its enzymatic activity. Therefore, the plausible existence of PA independent mode of action of LF including direct receptor mediated endocytosis or modulation of signal transduction cascade via unknown means is hypothesized. In silico protein docking analysis of other cellular receptors for any plausibility to play the role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = −773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.
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