Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential

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...

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Bibliographic Details
Published in:Oncotarget 2017-05, Vol.8 (22), p.35835-35847
Main Authors: Khandia, Rekha, Pattnaik, Bramhadev, Rajukumar, Katherukamem, Pateriya, Atul, Bhatia, Sandeep, Murugkar, Harshad, Prakash, Anil, Pradhan, Hare Krishna, Dhama, Kuldeep, Munjal, Ashok, Joshi, Sunil K
Format: Article
Language:English
Subjects:
Aged
Antigens, Bacterial - chemistry
Antigens, Bacterial - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Bacterial Toxins - chemistry
Bacterial Toxins - pharmacology
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Carcinoma, Ductal, Breast - drug therapy
Carcinoma, Ductal, Breast - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
Female
Humans
Middle Aged
Models, Molecular
Molecular Conformation
Neoplasm Staging
Protein Binding
Proto-Oncogene Proteins c-met - chemistry
Proto-Oncogene Proteins c-met - metabolism
Recombinant Proteins - chemistry
Recombinant Proteins - pharmacology
Research Paper
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.16214