AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells.

Differentiation therapy for cancer is a developing treatment modality that is based on the anti-proliferative effects associated with differentiation of the malignant cells. 1,25-dihydroxyvitamin D3 (1,25D) and its analogs are currently being evaluated clinically, alone or in combination with other agents, for treatment of several neoplastic diseases, but their usefulness as single agents may be limited by the enhancement of cell survival in some cell types exposed to 1,25D. In this study we evaluated the role of AKT signaling pathway, known to be anti-apoptotic in diverse cell types, in enhancing the survival of human leukemia HL60 cells induced to differentiate with 1,25D. We found that the phosphorylation and activity of AKT, as well as of its down-stream targets, are increased after the exposure to 1,25D. Treatment of HL60 cells with PI3K inhibitors LY294002 and Wortmannin, which decrease the activity of the AKT pathway, induced apoptosis, but this effect was reduced in cells simultaneously treated wi...