HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis

Autor: Xinya Jiang, Juan Du, Cheng Zhou, Hui-En Zhan, Peng Fang, Hui Liang, Jue Li, Hui Zeng, Yi Liu, Xuejun Xu, Qun He
Rok vydání: 2020
Předmět:
0301 basic medicine
Hydroxymethylglutaryl-CoA Synthase
Apoptosis
Bone Marrow Cells
HL-60 Cells
RM1-950
Mitochondrion
Endoplasmic Reticulum
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Downregulation and upregulation
hemic and lymphatic diseases
Cell Line
Tumor
medicine
Humans
GATA1 Transcription Factor
Pharmacology
Acute myeloid leukemia
Chemistry
Endoplasmic reticulum
Tunicamycin
Myeloid leukemia
General Medicine
Unfold protein response
Endoplasmic Reticulum Stress
Mitochondria
Leukemia
Myeloid
Acute
030104 developmental biology
medicine.anatomical_structure
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cytarabine
Unfolded protein response
Cancer research
Unfolded Protein Response
Bone marrow
HMGCS1
Therapeutics. Pharmacology
medicine.drug
Signal Transduction
Zdroj: Biomedicine & Pharmacotherapy, Vol 137, Iss, Pp 111378-(2021)
ISSN: 1950-6007
Popis: Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a key enzyme in the mevalonate pathway of cholesterol synthesis. Dysregulation of HMGCS1 expression is a common occurrence in many solid tumors. It was also found to be overexpressed in newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Previous study proved that HMGCS1 could induce drug-resistance in AML cells. However, the underlying mechanism how HMGCS1 contributed to chemoresistance remains elusive. Here, we confirmed that HMGCS1 inhibitor Hymeglusin enhanced cytarabine/Adriamycin (Ara-c/ADR) chemo-sensitivity in AML cells lines. Moreover, Ara-c-resistant HL-60 cells (HL-60/Ara-c) and ADR-resistant HL-60 cells (HL-60/ADR) were more sensitive to HMGCS1 inhibition than HL-60 cells. In addition, we demonstrated that the transcription factor GATA1 was the upstream regulator of HMGCS1 and could directly bind to the HMGCS1 promoter. After treatment of Tunicamycin (Tm), the number of mitochondria was increased and the damage of endoplasmic reticulum (ER) was reduced in bone marrow cells from AML-RR patients, compared to cells from AML-CR group. HMGCS1 protected mitochondria and ER under ER stress and up-regulated unfold protein response (UPR) downstream molecules in AML cells. In summary, we proved that HMGCS1 could upregulate UPR downstream components, protect mitochondria and ER from damage in AML cells under stress, therefore conferring drug resistance. Therefore, HMGCS1 could serve as a novel target for treatment of patients with intolerant chemotherapy and AML-RR patients.
Databáze: OpenAIRE
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