Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Mutual antagonistic interactions between retinoic acid-induced gene products and phosphatidylinositol 3-kinase induced signals determine tumor cell sensitivity to retinoids

DA Talmage PhD, Y Chen PhD, D Liu MSc, Y Cho PhD, AP Tighe PhD

Institute of Human Nutrition, Columbia University, New York, NY,

AIM. Vitamin A active compounds, referred to as retinoids, are effective antagonists of tumor progression. However, their effectiveness is limited largely to the progression phase of tumor progression. We are attempting to define the mechanism(s) by which retinoids inhibit the proliferative expansion of cancerous and pre-cancerous cells, and understand why retinoids are largely ineffective at inhibiting tumor growth. METHODS. We have used a well-defined oncogenic agent, the middle T antigen of mouse polyomavirus, to identify mitogenic signaling pathways that are subject to negative regulation by retinoids. We have used a variety of methods to identify retinoid-induced genes whose products regulate signaling through these pathways. RESULTS. Retinoids prevent transformation by inhibiting signaling downstream of activated phosphatidylinositol 3-kinase (PtdIns 3-kinase). This anti-oncogenic effect of retinoids is limited to tumor cells in which PtdIns 3-kinase signaling is critical for proliferation. Cells from mammary tumors induced by wild type polyomavirus are sensitive to the anti-proliferative effects of retinoids; cell lines from tumors induced by a mutant virus that is selectively unable to activate PtdIns 3-kinase are not. Similar results are seen in studies of human breast cancer cells. Four retinoid-induced cDNAs whose products cooperate to inhibit transformation have been cloned. These include p190GAP-AP, a novel gene, protein kinase Calpha, JIP-1d. P190GAP-AP helps inactivate small GTPases that are effectors of PtdIns 3-kinase. The novel gene's function is unknown but it necessary for the function of p190GAP-AP. Targets for PKCalpha and JIP-1d are being sought. CONCLUSIONS. Retinoids prevent transformation by inhibiting signaling pathways that are activated by PtdIns 3-kinase. Retinoids to not inhibit proliferation of tumor cells whose proliferation is not dependent on PtdIns 3-kinase signaling. In addition, constitutive activation of PtdIns 3-kinase dramatically impairs the function of RARalpha. We think that this inhibition may explain the defective retinoid signaling seen during the development of a number of human cancers.

KEY WORDS: nuclear receptors, cell cycle, signal transduction, Jun N-terminal kinase.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on differentiation therapy.