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Extending Cancer Research
CHORI Scientist Links the Role of S1P Lyase to Cancer in New PNAS Publication

There has always been a theoretical possibility that sphingosine 1-phosphate (S1P) metabolism and signaling, which promote cell proliferation and prevent apoptosis – or cell death – could be involved in cancer. A new study conducted by CHORI scientist Julie Saba, MD, PhD, now provides evidence of that link between cancer and S1P lyase (SPL), the enzyme responsible for breaking down S1P.

“We were interested in SPL because it’s the main enzyme that removes S1P from tissues in the body and it’s very highly expressed in intestinal cells,” explains Dr. Saba.

Previous studies by Dr. Saba’s group had also shown that an increase in SPL expression resulted in a corresponding increase in apoptosis, which was another clue that SPL could be a key player in cancer development. The new study, published in the October Proceedings of National Academy of Scientists (PNAS), demonstrates for the first time that SPL expression (increases) in response to cellular stress and promotes apoptosis.

“When the cells are stressed –such as by treatment with chemotherapy, radiation, or from hypoxia or other stress conditions, SPL expression makes the cells fail to survive,” says Dr. Saba.

“Now that could be a bad thing, but in many cases that’s a good thing. When cells are damaged or DNA is damaged, it’s important to undergo apoptosis and be cleared rather than sustaining mutations that could turn a cell into a cancer cell. That’s a healthy process and part of the body’s cancer surveillance system.”

The study also importantly identifies that SPL is down-regulated in human colorectal carcinomas (CRC) and mouse intestinal adenomas, suggesting that decreased levels of SPL allow cells to evade the normal signals that would tell them to die, instead of proliferating and becoming polyps.

While the study primarily characterizes the role of SPL and its mechanisms, the results also offer significant implications for utilizing this new knowledge about SPL as a potential tool in the treatment of cancer.

As Dr. Saba explains, “It goes hand in hand with the fact that SPL is down-regulated in cancer. If we can turn the SPL back on, we may be able to sensitize cells to chemotherapy and improve responsiveness. We believe, although we haven’t proven it yet, that SPL is turned off in reversible ways that we might be able to take advantage of in the early stages of cancer.”

Dr. Saba is the first to acknowledge that it’s premature to suggest SPL regulation is the next cancer therapy on the list. There is still a great deal of work to be done, such as determining whether eliminating SPL expression in mice leads to tumor development, studies which are already underway in the Saba lab. Nevertheless, it’s a hopeful turning point in cancer research that provides a glimmer of hope on the horizon.

“It’s promising, and the more we understand about this pathway in normal physiology and disease,” says Dr. Saba, “the more we’ll be able to look out for aberrations in the pathway and attempt to circumvent them.”

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Monday, May 16, 2011 11:33 PM

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