Unexpected role: EGFR protects cancer cells from starvingMay 06, 2008HOUSTON - A growth factor receptor found abundantly on the surface of cancer cells and long known to fuel cancer growth also protects tumor cells from starvation by a newly identified mechanism, researchers at The University of Texas M. D. Anderson Cancer Center report in the May 5 issue of Cancer Cell. The epidermal growth factor receptor (EGFR) stabilizes another cell membrane protein that channels a constant supply of glucose to cancer cells, saving them from devouring themselves, a team led by Isaiah J. Fidler, D.V.M., Ph.D., professor and chair of M. D. Anderson's Department of Cancer Biology, and Mien-Chie Hung, Ph.D., professor and chair of the department of Molecular and Cellular Oncology. Their findings could explain why some drugs that target what was previously thought to be EGFR's only role in cancer proliferation have had limited success in patients. Drugs that block EGFR's activation by growth factors - its tyrosine kinase activity -- have gotten response rates in 10 percent to 20 percent of patients across a variety of cancers. "We show that the receptor is active independent of its kinase activity," Fidler said. "Up until now everyone - including us - focused on kinase, kinase, kinase." The team shows that EGFR binds to another cell membrane protein called the sodium/glucose co-transporter (SGLT1), protecting SGLT1 from destruction by the cell's proteasome complex, Hung noted. "This complex stabilizes SGLT1 so it continues to transport glucose from the cell membrane into the cell," Hung said. A "terrific target" Cancer cells have a high metabolic rate and require more glucose to fuel their activities than do normal cells, Fidler said. "Inhibiting the kinase activity of the receptor does not interfere with EGFR stabilizing SGLT1, allowing cancer cells to maintain intracellular glucose levels," Fidler said. "To destroy tumor cells by depriving them of glucose one needs to interfere with the receptor per se rather than activation of the receptor. Whether we can target EGFR and therefore interfere with SGLT and therefore interfere with intracellular glucose remains to be seen, but it's a terrific target to shoot for." The team concludes that it may be necessary to knock down both EGFR's glucose-related role and its growth-inducing kinase activity in order to attack cancers of the epithelium - tissue that lines the surfaces and cavities of the body's organs. Epithelial cancers, or carcinomas, make up 80 percent of all cancers. EGFR resides on the surface of cell membranes, where epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-a) can bind to the receptor, launching a molecular phosphorylation cascade, which stimulates the cell to divide. This normal tyrosine kinase activity is put on overdrive in cancer cells because EGFR is heavily overexpressed on the cell's surface. Block EGFR and cancer cells die of self-cannibalization In the current research, the team looked at expression of EGFR but not its kinase activity. They found that blocking expression of the receptor with small interfering RNA killed prostate cancer cells. The cells did not die from apoptosis - programmed cell death that forces a defective cell to commit suicide by destroying its DNA complex and its energy-producing mitochondria. Rather, these cells died of autophagy - a self-cannibalization response in which a cell under stress or lacking nutrients devours part of its cytoplasm and other organelles to survive. When this response goes on long enough, the cell essentially eats itself until it dies. In cancer research, autophagy is thought to be a second type of programmed cell death. This self-eating response was also seen in breast cancer and colon cancer cells. Next, the team measured glucose levels in two sets of prostate cancer cells - one treated by a tyrosine kinase inhibitor and the other with EGFR knocked down by siRNA. Glucose levels were unaffected by the tyrosine kinase inhibitor but fell by 50 percent in the cells with EGFR blocked. The results held in breast and colon cancer cells. Increasing the level of glucose in the medium that held the cells halted autophagic cell death. These results pointed the team toward glucose transporting proteins. They found that when EGFR was knocked down in a cell, levels of SGLT1 also fell as did glucose levels, resulting in autophagic cell death. University of Texas M. D. Anderson Cancer Center |
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| Related Cancer Cells Current Events and Cancer Cells News Articles Feedback loop explains inflammatory effect on intestinal lining Signals released by immune cells during a bout of inflammatory bowel disease interfere with intestinal cells' ability to regenerate. Yet people with inflammatory bowel diseases have a significantly higher risk of developing colon cancer: a hyper-activation of growth in those same intestinal cells. Engineers: Weak laser can ignite nanoparticles, with exciting possibilities University of Florida engineering researchers have found they can ignite certain nanoparticles using a low-power laser, a development they say opens the door to a wave of new technologies in health care, computing and automotive design. Study shows further benefits of noscapine for prostate cancer New research has revealed a major breakthrough in the use of cough medicine ingredient noscapine as a prophylactic treatment for prostate cancer. ASTRO publishes supplement on protecting cancer patients by reducing radiation doses, side effects The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) review has been published in the International Journal of Radiation Oncology*Biology*Physics, the official journal of the American Society for Radiation Oncology (ASTRO) to update recommendations for the safe irradiation of 16 organs. Duke technique is turning proteins into glass Duke University researchers have devised a method to dry and preserve proteins in a glassified form that seems to retain the molecules' properties as workhorses of biology. Blocking cancer in its path: New cellular defect discovered UCSF researchers have discovered that a key cellular defect that disturbs the production of proteins in human cells can lead to cancer susceptibility. Cellular pathway could provide evidence of how cancer and obesity are linked The link between obesity and disease has been well documented. There's evidence now that obesity and cancer have a strong link, as they've shown in the United States at least 90,000 cancer deaths a year can be attributed to obesity. 3-D cell culture: Making cells feel right at home The film "Avatar" isn't the only 3-D blockbuster making a splash this winter. A team of scientists from Houston's Texas Medical Center this week unveiled a new technique for growing 3-D cell cultures, a technological leap from the flat petri dish that could save millions of dollars in drug-testing costs. The research is reported in Nature Nanotechnology. New cancer drug screening technique more closely mirrors reality Improving on traditional screening tests for potential anti-cancer drugs, scientists at Dana-Farber Cancer Institute have developed a laboratory technique that more closely simulates the real-world conditions in which tumor cells mingle with the body's normal cells. Human cells exhibit foraging behavior like amoebae and bacteria When cells move about in the body, they follow a complex pattern similar to that which amoebae and bacteria use when searching for food, a team of Vanderbilt researchers have found. More Cancer Cells Current Events and Cancer Cells News Articles |
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