Inhibition of CPT1a as a Prognostic Marker can Synergistically Enhance the Antileukemic Activity of ABT199
Abstract Background: Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the its prognostic value and possible treatment strategies on acute myeloid leukemia (AML).Methods: The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. western blot were used to measure the expression of Mcl-1.Results: In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P =0.01) and event free survival (P=0.032) compared to patients in low expression group (n =80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also performed a metabolomic analysis and observed a decrease of fatty acid in CPT1a high expression group comparing to low expression group, which confirms that CPT1a can facilitate FAO to provide energy fueling tumor growth. Moreover, we found downregulation of CPT1a sentitizes BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 has a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1.Conclusion: our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strongsynergistic inhibitory effects on AML.