Dichloroacetate Reprograms JunD Expression and Enhances Chemosensitivity in Acute Myeloid Leukemia via p53 Status

• Sana Belkahla

  Department of Biology, College of Science, King Faisal University, P.O.Box 400 Al-Ahsa, 31982, Saudi Arabia

The protein JunD plays an important role in cell proliferation, differentiation and apoptosis. In the context of leukemia, particularly acute myeloid leukemia, JunD overexpression has been implicated in disease progression and cell proliferation. However, JunD can also act as a tumor suppressor in certain cancer cases, thus making its role controversial. Here, we investigated the molecular mechanisms by which dichloroacetate (DCA) modulates JunD expression and its impact on chemosensitivity in acute myeloid leukemia (AML) cells, specifically focusing on the involvement of p53.

The results showed a significant reduction in JUND mRNA levels in OCI-AML3 (wt-P53) cells treated with 1 and 5 mM DCA (48±6.50 and 53±10.17%, respectively; p< 0.05) compared to untreated cells. On the other hand, in HL60 a P53-Null cell, a significant increase in JunD expression (132.7±6.02%; p< 0.05) was observed when compared to untreated cells. Similar results were observed in OCI-AML3 cells transfected with Si-P53 plasmid to reduce the expression of p53.

Additionally, JUND knockdown significantly decreased cell viability (compared to scramble Si-RNA) and further amplified the DCA effect (10.2±1.48%; p< 0.05). Similar results were noticed when cells were subjected to doxorubicin at different concentrations. In particular, the combination of DCA and doxorubicin resulted in enhanced anti-leukemic effects, indicating that JunD is essential for modulating the cellular response to doxorubicin.

Overall, we demonstrate for the first time that DCA decreased JunD expression and sensitized leukemic cells to chemotherapy, and these effects may depend on p53 status.

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