Journal
CELLULAR MICROBIOLOGY
Volume 23, Issue 8, Pages -Publisher
WILEY
DOI: 10.1111/cmi.13339
Keywords
cell cycle; cell cycle arrest; ExoT; immunotoxin; melanoma; Pseudomonas aeruginosa
Categories
Funding
- Bears Care Cancer Fund
- NIH grant R21 [R21 AI110685]
- Oncology Care Model (OCM) Cancer Award
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Research has shown that ExoT induces potent apoptotic cytotoxicity in cancer cell lines through two distinct mechanisms and significantly reduces tumor growth in melanoma. ExoT exhibits antiproliferative function in melanoma cells by causing cell cycle arrest in G1 interphase through dampening G1/S checkpoint proteins. Both domains of ExoT contribute to G1 cell cycle arrest in melanoma, with ADPRT likely involving the Crk adaptor protein.
Recently, we demonstrated that Pseudomonas aeruginosa Exotoxin T (ExoT) employs two distinct mechanisms to induce potent apoptotic cytotoxicity in a variety of cancer cell lines. We further demonstrated that it can significantly reduce tumour growth in an animal model for melanoma. During these studies, we observed that melanoma cells that were transfected with ExoT failed to undergo mitosis, regardless of whether they eventually succumbed to ExoT-induced apoptosis or survived in ExoT's presence. In this report, we sought to investigate ExoT's antiproliferative activity in melanoma. We delivered ExoT into B16 melanoma cells by bacteria (to show necessity) and by transfection (to show sufficiency). Our data indicate that ExoT exerts a potent antiproliferative function in melanoma cells. We show that ExoT causes cell cycle arrest in G1 interphase in melanoma cells by dampening the G1/S checkpoint proteins. Our data demonstrate that both domains of ExoT; (the ADP-ribosyltransferase (ADPRT) domain and the GTPase activating protein (GAP) domain); contribute to ExoT-induced G1 cell cycle arrest in melanoma. Finally, we show that the ADPRT-induced G1 cell cycle arrest in melanoma cells likely involves the Crk adaptor protein. Our data reveal a novel virulence function for ExoT and further highlight the therapeutic potential of ExoT against cancer.
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