Fighting dead zones of cancer
Almost all high-risk, poor-prognosis cancers have very low levels of oxygen in the primary tumor’s interior. A marker for this oxygen-depleted state is the presence of a protein known as H1FI alpha.
In healthy cells, HIF1 alpha is degraded into harmless nothingness in the cytoplasm. In low-oxygen cancer cells however, the normal breakdown goes awry and HiFl alpha is able to enter the nucleus, where it may activate genes that further promote aberrant cell growth.
A new study conducted by researchers at the University of California, San Diego School of Medicine shows that an emerging class of anticancer treatments known as PI-3K inhibitors help to degrade the HIF1 alpha protein and thus may offer a potential therapy for treating deadly hypoxic tumors. The study was published in a recent issue of the Journal of Biological Chemistry.
“Our main finding is that, in the absence of PI-3K signaling, MDM2 proteins cannot go inside the nucleus,” said lead author Shweta Joshi, PhD, postdoctoral researcher. “In the cytoplasm, the MDM2 proteins degrade HIF1 alpha. This is good news because it means that some new cancer therapies may help patients in more ways that was initially realized.”
"These HIF1 proteins are major players in driving the cancer state," said co-author Donald Durden, MD, PhD, professor and vice chair for Research in the Department of Pediatrics and research director, Division of Hematology/Oncology at the UC San Diego Moores Cancer Center. “They control degradation of surrounding tissues, induce a change in metabolism and induce the formation of blood vessels. That is why our observation is so important, because it reveals an entirely new way of HIF1 regulation.”
Pictured: A false-color, scanning electron micrograph of two cultured HeLa cancer cells, courtesy of Thomas Deerinck, National Center for Microscopy and Imaging Research at San Diego.