Understanding the Apoptotic Functions of IGFBP-3 in Prostate Cancer
Annual rept. 1 Nov 2005-31 Oct 2006
CALIFORNIA UNIV LOS ANGELES
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The IGF axis is known to play an important role in the epidemiology of many tumors. IGFBP-3 promotes apoptosis in cancer cells by both IGF-dependent and -independent mechanisms. We have previously shown that IGF3P-3 is rapidly internalized and localized to the nucleus where its interactions with the nuclear receptor RXRo are important in apoptosis induction. We demonstrate that phosphorylation of IGFBP-3 S156 by DNA-PK enhances its nuclear accumulation and is essential for its ability to interact with RXR and induce apoptosis in cultured prostate cancer cells. Indeed IGFBP-3-Si 56A is completely unable to induce apoptosis in 22RV1 prostate cancer cells. Using specific chemical inhibitors we investigated the contribution of other protein kinases to the regulation of IGFBP-3-induced apoptosis. Preventing the activation of CK2 enhanced the apoptotic potential of IGFBP-3. We mapped two potential CK2 phosphorylation sites in IGFBP-3 S167 and 5175. These sites were mutated to Ala and the resulting constructs were transfected in to LAPC4 and 22RV1 prostate cancer cells. WtIGFBP-3 and IGFBP-3-S175A induced apoptosis to a comparable extent however IGFBP-3-S167A was far more potently apoptosis-inducing. Together these data reveal two key regulatory phosphorylation sites in the central region of IGFBP-3. Phosphorylation of 5156 by DNA-PK promotes apoptosis whilst phosphorylation of 5167 by CK2 limits the ability of IGFBP-3 to induce apoptosis. These studies reveal multi-site phosphorylation of IGFBP-3 that both positively and negatively regulate its apoptotic potential. Understanding such intrinsic regulation of IGF3P-3 action may enhance the development of potential cancer therapies.
- Anatomy and Physiology
- Medicine and Medical Research