PNAS: How A Stuck Accelerator Causes Cancer Cell Expansion

Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 27 Sep 2008 - 0:00 PDT

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The cellular oncogenes and tumor suppressor genes are analogous to the accelerator and brake pedals in a car. If an oncogene is permanently active, similar to a stuck accelerator in a car, cells divide without restraints and a tumor develops. The c-MYC proto-oncogene is activated aberrantly in about 50% of all tumors. As a result the c-MYC protein is produced in excessive amounts, which in turn activates processes associated with cell proliferation. A group of research scientists led by Prof. Heiko Hermeking (Institute of Pathology, Ruhr-University Bochum, Germany) has now identified a mechanism that allows c-MYC to drive cellular proliferation in the presence of substances that would lead to a block in cell division in normal cells, as for example chemotherapeutic agents. "In future this knowledge may allow a more specific inhibition of tumor growth" Hermeking hopes. This study has been published in the current edition of the Proceedings of the National Academy of Sciences USA (PNAS).

Attractive target structure for cancer drugs

The c-MYC gene is a nodal point in the regulation of cellular division and is highly expressed in colorectal cancer and many other tumor types. The c-MYC protein is a transcription factor which regulates other genes, which in turn mediate the effects of c-MYC on cell proliferation. "In order to understand the origin of cancer it is therefore important to identify genes and mechanisms that mediate the effects of c-MYC on cells" Prof. Hermeking explained. Because of its central position in the regulation of cell proliferation c-MYC is an attractive target structure for cancer therapeutic agents.

Signaling chain unraveled in detail

Prof. Hermeking's research team determined how c-MYC promotes proliferation. They were able to demonstrate that c-MYC activates the AP4 gene, which results in the synthesis of AP4 protein. AP4 protein in turn suppresses the formation of a central inhibitor of cellular division (p21) by occupying its regulatory region within the genome. Thereby tumor cells become refractory to substances, e.g. chemotherapeutic agents, which block cell division in normal cells. Instead of terminating proliferation the tumor cells undergo cell death. Moreover, the scientists discovered that colorectal carcinomas, in contrast to normal colon tissue, generally produce large amounts of the AP4 protein. In the future, the knowledge about this signaling cascade could enable a more targeted prevention of cancer cell proliferation. The project is supported by the German Cancer Aid (Deutsche Krebshilfe e.V.).

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