PEA-15, a protein previously shown to slow ovarian tumor growth and spread of the cancer, can alternatively enhance tumor formation in kidney cells that have a mutation in a cancer-promoting gene called H-Ras. These are the findings of a study from the University of Hawaii Cancer Center.
The H-Ras oncogene is mutated in many human malignancies, and previous reports have shown the ability of H-Ras to contribute to the development, proliferation and metastasis of these tumors. Conversely, PEA-15 had been reported to inhibit tumor cell proliferation and metastasis by opposing H-Ras signals. In ovarian and breast cancer, PEA-15 is proposed to have promising therapeutic potential and in ovarian cancer PEA-15 has shown promise as a marker of prolonged patient survival.
This new study is the first finding of a pro-cancer effect of PEA-15 on proliferation and as such suggests caution in pursuing the use of PEA-15 as an anti-cancer therapeutic. The study results were published online today in the journal Oncogene
"Our findings reveal a surprising mechanism by which PEA-15 can enhance H-Ras driven transformation of cells, rather than stop it," said Joe W. Ramos, Ph.D., associate professor at the University of Hawaii Cancer Center and co-director of its Cancer Biology Program. "We showed that in a common scenario in which a cell contains a Ras mutation, PEA-15 can accelerate the rate of tumor formation both in vitro and in vivo," he added.
In contrast to reports suggesting a tumor-suppressor function of PEA-15, Ramos said the discovery confirms that PEA 15 expression can also trigger tumor growth. "What we now know is that PEA-15 can either enhance or impair the formation of tumors depending on the signaling pathways active in a specific tumor cell."
"As with most cancers, an interplay of factors determines the fate of a patient," noted Florian Sulzmaier, a researcher at the UH Cancer Center and first author of the newly published study. "PEA-15 might still be worth considering for treatment of certain cancers. However, care should be taken in tumor types that carry Ras mutations that could change the outcome of a therapy."
The article, PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase , appeared in today's online edition of Oncogene
. Ramos' colleagues included researchers from the University of Hawaii, the Cancer Institute of New Jersey and the Academic Medical Center, University of Amsterdam, The Netherlands.
This study was supported by a grant from the National Institutes of Health National Cancer Institute and National Institute of General Medicine, and the Victoria S. and Bradley Geist Foundation.