Blockade of p38 MAPK overcomes AML stem cell line KG1a resistance to 5-Fluorouridine and the impact on miRNA profiling

Abstract

Most of the AML patients in remission develop multidrug resistance after the first-line therapy and relapse. AML stem cells have gained attention for their chemoresistance potentials. Chemoresistance is a multifactorial process resulting from altered survival signaling pathways and apoptosis regulators such as MAPK, NF-κB activation and ROS production. We targeted the survival pathway p38 MAPK, NF-κB and ROS generation in human chemoresistant AML stem cell line KG1a, susceptible to enhance cell sensitivity to the chemotherapy drug 5-Fluorouridine, compared to the chemosensitive AML cell line HL60. After confirming the phenotypic characterization of KG1a and HL60 cells using flow cytometry and transcriptomic array analyses, cell treatment with the NF-κB inhibitor IKKVII resulted in a complete induction of apoptosis, and a few p38 MAPK inhibitor SB202190-treated cells underwent apoptosis. No change in the apoptosis status was observed in the ROS scavenger N-acetylcysteine-treated cells. The p38 MAPK pathway blockade enhanced the KG1a cell sensitivity to 5-Fluorouridine, which was associated with the upregulation of microribonucleic acid-(miR-)328-3p, as determined by the microarray-based miRNA transcriptomic analysis. The downregulation of the miR-210-5p in SB202190-treated KG1a cells exposed to FUrd was monitored using RT-qPCR. The miR-328-3p is known for the enhancement of cancer cell chemosensitivity and apoptosis induction, and the downregulation of miR-210-5p is found in AML patients in complete remission. In conclusion, we highlighted the key role of the p38 MAPK survival pathway in the chemoresistance capacity of the AML stem cells and potentially involved miRNAs, which may pave the way for the development of a new therapeutic strategy targeting survival signaling proteins and reduce the rate of AML relapse.

Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling

“…The activation of the p38 MAPK pathway plays a critical role in orchestrating a range of cellular stresses, growth, and survival of tumor cells. , p38 MAPK is often increased and/or overactivated in AML blasts and represents an important pharmacological target. − However, selective p38 MAPK inhibitors have limited efficacy and for a variety of clinical indications none have progressed to Phase III . Losmapimod (known as GW856553 or GSK-AHAB) is a selective, potent, and orally MAPK14 (p38α MAPK) ATP competitive inhibitor used in several clinical trials (Table S1).…”

A Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling

“…39,40 p38 MAPK is often increased and/or overactivated in AML blasts and represents an important pharmacological target. [41][42][43] However, selective p38 MAPK inhibitors have limited efficacy and for a variety of clinical indications none have progressed to Phase III. 44 Losmapimod (known as GW856553 or GSK-AHAB) is a selective, potent, and orally MAPK14 (p38α MAPK) ATP competitive inhibitor 45 (Figure 1A) used in several clinical trials (Table S1).…”

A comprehensive analysis of cell‐autonomous and non‐cell‐autonomous regulation of myeloid leukemic cells: The prospect of developing novel niche‐targeting therapies

“…The cellautonomous role of the p38 MAPK signaling pathway in myeloid leukemia is also under investigation. Matou-Nasri et al (2022) underscored the role of the p38 MAPK pathway in the survival of AML cells.…”

“…The cell‐autonomous role of the p38 MAPK signaling pathway in myeloid leukemia is also under investigation. Matou‐Nasri et al (2022) underscored the role of the p38 MAPK pathway in the survival of AML cells. They showed that treating KG1a cells with SB202190, a p38 MAPK inhibitor, promoted apoptosis of the LCs and increased their sensitivity toward 5‐fluorouridine (Matou‐Nasri et al, 2022).…”

“…Matou‐Nasri et al (2022) underscored the role of the p38 MAPK pathway in the survival of AML cells. They showed that treating KG1a cells with SB202190, a p38 MAPK inhibitor, promoted apoptosis of the LCs and increased their sensitivity toward 5‐fluorouridine (Matou‐Nasri et al, 2022). In another study, Vaidya et al (2008) showed that the inhibition of p38 MAPK in LCs, both cell lines, namely, KG1a and HL60 and primary AML blasts, leads to the activation of p44/42 MAPK pathway in them and sensitizes them to the mitotic agent 5‐fluorouracil (5‐FU).…”