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 prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML). Methods The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients 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 was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis. Results In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had 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 strong synergistic inhibitory effects on AML.

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

“…Among the increased proteins following RBPMS knockdown, the two ARRB members—ARRB1 and ARRB2—are deregulated in many cancer types and have been linked to the inhibition of the senescence and growth as well as the promotion of the self-renewal, progression, and invasion of cancerous cells [ 39 , 40 , 81 ]. Moreover, CPT1A plays a crucial role in radioresistant and chemoresistant phenotypes in diverse cancer types [ 41 , 42 , 82 ]. Equally, altered protein levels of FLNA, HSPA7, HGF, ERO1A, and GARS1, have been related to cancer migration, adhesion, poor patient prognosis, and metastasis [ 48 , 49 , 50 , 83 , 84 ].…”

Targeting Energy Metabolism in Cancer Treatment

“…In addition, ST1326 demonstrated anti-tumor activity against several leukemia cell lines as well as cells obtained from patients with hematological malignancies [ 275 , 276 ]. Moreover, in AML studies, the synergistic effect of ST1326 with the inhibitor Bcl-2 ABT199 was noted [ 277 ]. Another CPT1 inhibitor with a limited number of scientific reports in the context of anti-cancer activity is oxfenicine (S-4-OH-phenyl-glycine) [ 278 ].…”

Progress of potential drugs targeted in lipid metabolism research

“…High-grade serous ovarian cancer (HGSOC) is the most common and lethal form of ovarian cancer, often diagnosed at an advanced stage, and most patients are platinum-resistant (Cannistra, 2004;Matulonis et al, 2016). A recent study in Cell Reports Medicine showed that targeting cpt1a with platinum-based chemotherapy can improve platinum resistance, although the molecular mechanism is currently unclear (Huang et al, 2021).…”

“…Teglicar differs from etomoxir in that it has high selectivity against CPT1A and is reversible, while etomoxir has no significant selectivity against CPT1A and CPT1B and partially inhibits CPT2 (Giannessi et al, 2003). Studies have shown that the combination of ST1326 and ABT199 (Bcl-2 inhibitor) can enhance the anti-acute myeloid leukemia (AML) effect of the latter, indicating that cpt1a may become a potential drug target for the treatment of AML (Ricciardi et al, 2015;Mao et al, 2021). Huntington's disease (HTT) is a severe neurodegenerative disease, and a Drosophila HTT disease model was used to demonstrate that treatment with the cpt1a inhibitor ST1326 can alleviate the symptoms of HTT (Bertapelle et al, 2022).…”