Methylcrotonyl-CoA carboxylase subunit 1 (MCCA) regulates multidrug resistance in multiple myeloma.

Abstract

AIMS:

This study aimed to investigate the effect and mechanism of methylcrotonyl-CoA carboxylase subunit 1 (MCCA) on multidrug resistance in multiple myeloma (MM).

MATERIALS AND METHODS:

The apoptosis kit and CCK-8 reagent were used to detect drug-induced cell apoptosis and viability. Immunoprecipitation, immunofluorescence staining, and protein structural simulation were used to detect the interaction between MCCA and Bad. Immunodeficient mice were injected with ARD cells and treated with bortezomib. Changes in tumor burden were recorded by bioluminescence imaging, and κ light chain content in the blood of mice was detected by enzyme-linked immunoassay.

KEY FINDINGS:

Patients with high MCCA expression from a primary MM dataset had superior overall survival. After treatment with different anti-MM drugs, MCCA knockdown MM (MCCA-KD) cells had higher survival rates than control knockdown (CTR-KD) cells (p < 0.05). Mechanistic studies have revealed that MCCA-KD cells had dysfunctional mitochondria with decreased Bax and Bad levels and increased Bcl-xl and Mcl-1 levels. Furthermore, that MCCA and Bad demonstrated protein-protein interactions. The half-life of Bad in MCCA-KD cells is significantly shorter than that in CTR-KD cells (7.34 vs. 2.42 h, p < 0.05). In a human MM xenograft mouse model, we confirmed that MCCA-KD tumors had a poor response to anti-MM drugs in vivo. Finally, we showed that MCCA might contribute to multidrug resistance in different human cancers, particularly in solid tumors.

SIGNIFICANCE:

Our findings demonstrated a novel function of MCCA in multidrug resistance. The lack of MCCA expression promoted antiapoptotic cell signaling in MM cells.

• Authors: Yu Feng, Jingcao Huang, Fangfang Wang, Zhimei Lin, Hongmei Luo, Qian Li, Xin Wang, Xiang Liu, Xinyu Zhai, Qianwen Gao, Lingfeng Li, Yue Zhang, Jingjing Wen, Li Zhang, Ting Niu, Yuhuan Zheng
• Journal: Life sciences (Life Sci) Vol. 333 Pg. 122157 (Nov 15 2023) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 37805164 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Inc.

Chemical References

• tiglyl-coenzyme A
• Acyl Coenzyme A
• Bortezomib

Topics

• Humans
• Animals
• Mice
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Acyl Coenzyme A (pharmacology, therapeutic use)
• Bortezomib (pharmacology)
• Apoptosis
• Cell Line, Tumor
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm