Metallo-protease Peptidase M84 from Bacillus altitudinis induces ROS-dependent apoptosis in ovarian cancer cells by targeting PAR-1
Niraj Nag,
Tanusree Ray,
Rima Tapader,
Animesh Gope,
Rajdeep Das,
Elizabeth Mahapatra,
Saibal Saha,
Ananda Pal,
Parash Prasad,
Amit Pal
Affiliations
Niraj Nag
Division of Molecular Pathophysiology, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India
Tanusree Ray
Division of Molecular Pathophysiology, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India
Rima Tapader
Division of Molecular Pathophysiology, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India
Animesh Gope
Division of Clinical Medicine, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India
Rajdeep Das
Molecular Cell Biology of Autophagy Lab, The Francis Crick Institute, 1, Midland Road, London NW1 1AT, UK
Elizabeth Mahapatra
Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India
Saibal Saha
Division of Molecular Pathophysiology, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India
Ananda Pal
Division of Clinical Medicine, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India
Parash Prasad
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital and Medical Center, 3333 Burnet Avenue, Cincinnati 45229-3026, OH, USA
Amit Pal
Division of Molecular Pathophysiology, ICMR-National Institute of Cholera and Enteric Diseases (ICMR-NICED), P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, West Bengal 700010, India; Corresponding author
Summary: We have purified Peptidase M84 from Bacillus altitudinis in an effort to isolate anticancer proteases from environmental microbial isolates. This metallo-protease had no discernible impact on normal cell survival, but it specifically induced apoptosis in ovarian cancer cells. PAR-1, a GPCR which is reported to be overexpressed in ovarian cancer cells, was identified as a target of Peptidase M84. We observed that Peptidase M84 induced PAR-1 overexpression along with activating its downstream signaling effectors NF-κB and MAPK to promote excessive reactive oxygen species (ROS) generation. This evoked apoptotic death of the ovarian cancer cells through the intrinsic route. In in vivo set-up, weekly intraperitoneal administration of Peptidase M84 in syngeneic mice significantly diminished ascites accumulation, increasing murine survival rates by 60%. Collectively, our findings suggested that Peptidase M84 triggered PAR-1-mediated oxidative stress to act as an apoptosis inducer. This established Peptidase M84 as a drug candidate for receptor mediated targeted-therapy of ovarian cancer.
