2. Academic Validation
  3. HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis

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

  • Biomed Pharmacother. 2021 May;137:111378. doi: 10.1016/j.biopha.2021.111378.
Cheng Zhou 1,  Jue Li 2,  Juan Du 3,  Xinya Jiang 1,  Xuejun Xu 2,  Yi Liu 2,  Qun He 2,  Hui Liang 2,  Peng Fang 2,  Huien Zhan 4,  Hui Zeng 5
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China; Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 2 Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 3 Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China.
  • 4 Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China. Electronic address: [email protected].
  • 5 Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China. Electronic address: [email protected].
PMID: 33601148 DOI: 10.1016/j.biopha.2021.111378
Abstract

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.

Keywords

Acute myeloid leukemia; Endoplasmic reticulum; HMGCS1; Mitochondria; Unfold protein response.

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