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Vitamin D3 causes potent suppression of various cancer cells; however, significant supraphysiological concentrations of this compound are required for antineoplastic effects. Current combinatorial therapies with vitamin D3 are restricted to differentiation effects. It remains uncertain if autophagy is involved in vitamin D3 inhibition on leukemia cells. Here we show that besides triggering differentiation and inhibiting apoptosis, which was previously known, vitamin D3 triggers autophagic death in human myeloid leukemia cells. Inhibiting differentiation does not efficiently diminish vitamin D3 suppression on leukemia cells. Vitamin D3 up-regulates Beclin1, which binds to class III phosphatidylinositol 3-kinase to trigger autophagy. Vitamin D3 phosphorylates Bad in its BH3 domain, resulting in disassociation of the apoptotic Bad-Bcl-xL complex and association of Bcl-xL with Beclin1 and ultimate suppression of apoptotic signaling. Knockdown of Beclin1 eliminates vitamin D3-induced autophagy and inhibits differentiation but activates apoptosis, suggesting that Beclin1 is required for both autophagy and differentiation, and autophagy cooperates with differentiation but excludes apoptosis, in which Beclin1 acts as an interface for these three different cascades. Moreover, additional up-regulation of autophagy, but not apoptosis, dramatically improves vitamin D3 inhibition on leukemia cells. These findings extend our understanding of the action of vitamin D3 in antineoplastic effects and the role of Beclin1 in regulating multiple cellular cascades and suggest a potentially promising strategy with a significantly better antileukemia effect.1,25-Dihydroxyvitamin D3, the hormonally active form of vitamin D3, plays critical roles in regulating cellular and physiological responses. Treatment of vitamin D3 potently inhibits cell proliferation in a wide range of cancer cells, including myeloid leukemia and carcinomas of the breast, prostate, colon, skin, and brain and inhibits angiogenesis, tumor invasion, and metastases (1-8), suggesting that vitamin D3 has potential applications in cancer prevention and treatment. Vitamin D3 is known to inhibit cancer cell proliferation through the induction of differentiation, which is dependent on the signaling mechanisms involving down-regulation of Akt and its disassociation with Raf1 and subsequent activation of Raf/MEK/ERK 2

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