HucMSC exosomes promoted imatinib-induced apoptosis in K562-R cells via a miR-145a-5p/USP6/GLS1 axis

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with increasing incidence worldwide. Growing evidence suggests that ubiquitin-specific proteases (USPs) play a role in cancer treatment. Dysregulation of miR-146a has been found in both adult and pediatric patients with acute leukemia. Knockdown of glutaminase-1 (GLS1) resulted in inhibition of tumor growth. However, the role of miR-146a-5p/USP6/GLS1 in leukemia and chemoresistance of leukemia cells remains to be elucidated. In the current study, USP6 level was increased in bone marrow aspiration specimens of patients with CML and associated with poor prognosis. USP6 was significantly upregulated in imatinib (IM)-resistant clinical samples compared with IM-sensitive samples. USP6 overexpression significantly inhibited IM-induced apoptosis of leukemia cells. Overexpressing USP6 significantly increased GLS1 ubiquitination to decrease GLS protein. A mechanism study indicated that USP6 regulation of IM resistance of CML cells was GLS1 dependent and regulated by miR-146a-5p. Administration of human umbilical cord mesenchymal stem cell (hucMSC) exosomes promoted IM-induced cell apoptosis through miR-145a-5p/USP6. Therefore, hucMSC exosomes promoted IM-induced apoptosis of K562-R cells by suppressing GLS1 ubiquitination to increase GLS protein via miR-146a-5p and its target GLS1. The findings highlight the importance of miR-146a-5p/USP6/GLS1 signaling in chemoresistance of leukemia and provide new insights into therapeutic strategies for chemoresistant leukemia.

Analysis of the Inhibitory Effect of hsa-miR-145-5p and hsa-miR-203a-5p on Imatinib-Resistant K562 Cells by GC/MS Metabolomics Method

“…MiRNAs have been recognized as key regulators of cancer chemoresistance. Previous studies have reported that hsa-miR-145-5p and hsa-miR-203a-5p hold the ability to overcome IM resistance in CML cells. − Likewise, the efficacy of these two miRNA mimics in overcoming IM resistance has been verified in our previously published study . The study utilized the MTT assay to assess the effects of hsa-miR-145-5p and hsa-miR-203a-5p, both individually and in combination with IM (IM + hsa-miR-145-5p and IM + hsa-miR-203a-5p).…”

“…So based on the last publication, our current objective is to investigate several other metabolic pathways in addition to the glutathione metabolism that may also contribute to the development of IM resistance. Moreover, we investigated whether the reversion of IM resistance following hsa-miR-145-5p or hsa-miR-203a-5p transfection might be linked to a reversal of the metabolic profile, referencing findings from various studies where the enforced expressions of these miRNAs resulted in the reversal of IM resistance in leukemic cells. − …”

Exosomal circ_0037104 derived from Hu‐MSCs inhibits cholangiocarcinoma progression by sponging miR‐620 and targeting AFAP1

“…For example, microRNA-503-3p, microRNA-431-5p, and miR-145a-5p in exosomes of MSC can play a role in suppressing tumors. [25,41,42] However, whether circRNAs in exosomes also plays a role in anticancer activity is currently unclear. Next, we found that the expression of circ_0037104 was significantly reduced in CCA, which could significantly inhibit the occurrence and development of CCA.…”

Tumour‑derived exosomes and their emerging roles in leukaemia (Review)

“…IM serves an important role in CML treatment and IM resistance is also an obstacle to CML treatment. A previous study showed that ubiquitin-specific protease is significantly up-regulated in IM-resistant clinical samples; miR-146a-5p down-regulated the IM resistance of CML, human umbilical cord mesenchymal stem cell-derived exosomes can promote IM-induced apoptosis through miR-145a-5p/USP6,indicating the potential role of miR-146a-5p in leukaemia chemoresistance ( 94 ). A study has confirmed that miR-328 is significantly decreased in IM-resistant patients, where overexpression of miR-328 sensitizes drug-resistant tumour cells to IM.…”