Metallo-protease Peptidase M84 from Bacillusaltitudinis 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

doi:10.1016/j.isci.2024.109828

Metallo-protease Peptidase M84 from Bacillusaltitudinis induces ROS-dependent apoptosis in ovarian cancer cells by targeting PAR-1

iScience. 2024 Apr 26;27(6):109828. doi: 10.1016/j.isci.2024.109828. eCollection 2024 Jun 21.

Authors

Affiliations

¹ 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.
² 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.
³ Molecular Cell Biology of Autophagy Lab, The Francis Crick Institute, 1, Midland Road, London NW1 1AT, UK.
⁴ Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal 700026, India.
⁵ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital and Medical Center, 3333 Burnet Avenue, Cincinnati 45229-3026, OH, USA.

Abstract

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.

Keywords: Cancer; Molecular biology.