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MSc. 1993; University of London, UK.
Thesis Advisor: Dr. George P. Studzinski
Department: Pathology and Laboratory Medicine
Thursday, April 29, 2010
It is known that the interaction of the vitamin D metabolite (1,25D) with its functional vitamin D receptor (VDR) leads to differentiation, G1 arrest, and increased cell survival in p53-null acute myeloid leukemia (AML) cells. However, there are no reports on the effect of 1,25D in leukemia cells expressing wild-type p53. Here, we examined vitamin D signaling in AML cells, MOLM-13 and OCI-AML3 expressing wild-type p53. We also investigated if the G1 cell cycle block associated with monocytic differentiation is modulated by the p53 status of the cells treated with 1,25D, alone or with plant antioxidants carnosic acid (C) or silibinin (S), and a p38 MAPK inhibitor SB202190 (SB), a combination (D-C/S-SB) previously shown to enhance differentiation of AML p53null cells. D-C/S-SB enhanced differentiation of OCI-AML3 (p53wt) and as expected HL60 (p53null) cells, but not of MOLM-13 cells. Conversely, MOLM-13 cells treated with 1,25D and/or D-C/S-SB, resembled HL60 cells in rapid G1 block, while OCI-AML3 cells showed a delayed G1 block when treated in a similar way, indicating that there is no relationship between the p53 status and G1 block. Interestingly, the increased levels of p21Cip1/Waf1 were insufficient to promote a G1 block in this system, as only cell lines with increased levels of p27Kip1 and p35Nck5a, an activator of Cdk5, showed a rapid G1 block. Overall, our data show that the p53-p21 axis is unlikely to have a role in differentiation-associated G1 block in AML cells with wild-type p53.
The tumor suppressor p53 is often referred to as “the guardian of the genome” due to its central role in the cellular response to oncogenic stress and prevention of tumor development. Mutations of p53 in acute myeloid leukemia are rare but resistance to chemotherapy has been reported due to deregulation of the p53 signaling and differentiation pathways. Therefore, we also examined vitamin D signaling of cell survival in MOLM-13 and OCI-AML3 in the presence and absence of the MDM2 antagonist nutlin-3a. Combination of nutlin-3a with 1,25D accelerated programmed cell death, likely due to enhanced nutlin-induced upregulation of the pro-apoptotic PIG-6 protein and downregulation of anti-apoptotic BCL-2, MDMX, human kinase suppressor of Ras 2 (hKSR2) and p-ERK2. Our study suggests that vitamin D may enhance the activity of a novel class of antitumor agents, the MDM2 antagonists.