Bacterial Toxin Shows Promise as Potential Anticancer Drug

MARTX toxins serve as delivery platforms for cytotoxic effector domains. One of these effector domains, called the domain of unknown function in position 5 (DUF5), has been shown to increase the potency of the V. vulnificus MARTX toxin in mouse virulence studies, indicating DUF5 directly contributes to pathogenesis. DUF5 is localized in the plasma membrane dependent upon its C1 domain, and the cells become rounded dependent upon its C2 domain.

In the current study, investigators at Northwestern University (Chicago, IL, USA) used a combination of genetic, cell biological, and biochemical strategies to probe the mechanism of action of the MARTX C2 domain, to understand the connection of DUF5 to both cytotoxicity and increased virulence of the pathogen.

They reported in the June 8, 2015, online edition of the journal Nature Communications that DUF5 was a site-specific endopeptidase that cleaved both Ras and the closely related small GTPase Rap1. Both proteins are critical for activation of the innate immune response during infection, which explains the crucial role of this effector domain in the increased virulence of V. vulnificus strains that have DUF5.

In addition, the investigators showed that the V. vulnificus MARTX protein could inhibit cancer cell growth by deactivating Ras. This linkage seems justified, as Ras signaling stimulates cell growth and division, and overactive Ras signaling can ultimately lead to cancer. Ras is the most common oncogene in human cancer—mutations that permanently activate Ras are found in 20%–25% of all human tumors and up to 90% in certain types of cancer such as pancreatic cancer.

"What is unique about this study is the ability of the toxin to cleave Ras, rather than modify it, which is a novel mechanism for inactivating Ras," said senior author Dr. Karla Satchell, professor of microbiology and immunology at Northwestern University. "Ras is important for cell proliferation in cancer, so the toxin could potentially be developed as a treatment for different types of tumors. It has been known that Ras has a role in cancer development, and targeting Ras has been one of the hardest challenges of cancer research and drug discovery."

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