Unexpected role: EGFR protects cancer cells from starving

"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.

Grants from the National Cancer Institute supported this research, including M. D. Anderson's Specialized Program of Research Excellence (SPORE) in Prostate Cancer and its SPORE in Breast Cancer. First author Zhang Weihua, Ph.D., was partially supported by an Odyssey Fellowship Award from The University of Texas M.D. Anderson Cancer Center.

Co-authors with Fidler, Hung and Weihua are Rachel Tsan and Qiuyu Wu, both of Department of Cancer Biology; and Wei-Chien Huang and Chao-Hwa Chiu, both of the department of Molecular and Cellular Oncology.