January 3, 2007
According to American Cancer Society estimates, nearly 31,000 Americans were diagnosed with head and neck cancer this year. As part of their treatment, most were referred to a radiation oncologist to have the area in and around the tumor irradiated twice daily for up to seven weeks. The problem is salivary glands often are clustered within the field of treatment. The ambient radiation severely damages the glands, and studies indicate that the typical head-and-neck cancer patient has up to a 60-percent reduction in salivary flow during the first week of treatment alone. Often their remaining saliva has a ropy, viscous quality, and patients must battle with a parched and/or burning oral sensation, difficulty chewing and swallowing, halitosis, and a range of other unwanted side effects.
As researchers have formulated new strategies to spare the salivary glands during treatment, they continue to grapple with a key biological question: Do a large percentage of salivary gland cells respond to the excess radiation by triggering apoptotic pathways and committing suicide? If so, it may be possible to suppress the suicide signals during radiation treatment and allow more cells in the salivary glands to survive. In the December issue of the journal Molecular and Cellular Biology, a team of NIDCR grantees and colleagues add needed new molecular details to a potential cell-suicide suppression signal. In studies with transgenic mice, the scientists first showed that gamma irradiation does indeed induce apoptosis of the saliva-producing acinar cells of the parotid and submandibular salivary glands. They then found that salivary cells that expressed an active form of the enzyme Akt1 can chemically stop the much-studied gatekeeper protein p53 from signaling apoptosis. Akt phosphorylates and stabilizes MDM2 which results in lower levels of p53. The drop in p53 activity results in lower expression of genes involved in the apoptotic process. Interestingly, if the active form of Akt1 protein was expressed but the scientists reduced the levels of MDM2, they found that the salivary acinar cells were susceptible to drug-induced apoptosis. This indicates that MDM2 is “a critical substrate” of activated Akt1 in suppressing p53 signaled apoptosis.