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Research Articles: Therapeutics, Targets, and Development

Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis

Departments of ¹ Pharmacology and Therapeutics and ² Cancer Genetics, Roswell Park Center Institute, Elm and Carlton Streets, Buffalo, New York; ³ OSI Pharmaceuticals, Broadhollow Bioscience Park, Farmingdale, New York; and ⁴ University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Requests for reprints: Michael G. Brattain, Department of Pharmacology and Therapeutics, Roswell Park Center Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3044; Fax: 716-845-8857. E-mail: michael.brattain{at}roswellpark.org

Abstract

PIK3CA, encoding the p110 catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival. [Mol Cancer Ther 2007;6(3):1143–50]

Grant support: NIH grants CA 34432, CA54807, and CA 16056.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 8/06; revised 12/21/06; accepted 1/31/07.

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