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

Chen, Xiaowen1,2; Chen, Yixin3,4; Zhang, Min1,2; Cheng, Hui5; Mai, Huirong1; Yi, Meng1; Xu, Huanli1; Yuan, Xiuli1; Liu, Sixi1; Wen, Feiqiu1,2

2022-01-28

10.1038/s41419-022-04531-3

Cell Death & Disease   影响因子和分区

2041-4889

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.

SCI

英语

其他

Science and Technology Project from the Science Technology and Innovation Committee of Shenzhen Municipality[JCYJ20170817170110940] ; Sanming Project of Medicine in Shenzhen[SZSM201512033] ; Shenzhen Industry and Information Committee "Innovation Chain and Industry Chain" integration special support plan project[20180225103240819] ; Shenzhen Fund for Guangdong Provincial High level Clinical Key Specialties[SZGSP012]

Cell Biology

Cell Biology

WOS:000749206300001

SPRINGERNATURE

Web of Science

1.Shenzhen Childrens Hosp, Dept Hematol & Oncol, Shenzhen 518038, Peoples R China
2.Shenzhen Childrens Hosp, Shenzhen Inst Pediat, Shenzhen 518038, Peoples R China
3.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Dept Oncol, Shenzhen 518020, Peoples R China
4.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
5.Naval Mil Med Univ, Changhai Hosp, Dept Hematol, Shanghai 200433, Peoples R China

Chen, Xiaowen,Chen, Yixin,Zhang, Min,et al. HucMSC exosomes promoted imatinib-induced apoptosis in K562-R cells via a miR-145a-5p/USP6/GLS1 axis[J]. Cell Death & Disease,2022,13(1).

Chen, Xiaowen.,Chen, Yixin.,Zhang, Min.,Cheng, Hui.,Mai, Huirong.,...&Wen, Feiqiu.(2022).HucMSC exosomes promoted imatinib-induced apoptosis in K562-R cells via a miR-145a-5p/USP6/GLS1 axis.Cell Death & Disease,13(1).

Chen, Xiaowen,et al."HucMSC exosomes promoted imatinib-induced apoptosis in K562-R cells via a miR-145a-5p/USP6/GLS1 axis".Cell Death & Disease 13.1(2022).