Proline promotes proliferation and drug resistance of multiple myeloma by downregulation of proline dehydrogenase

Jingyu Zhang; Fangming Shi; Xing Liu; Xuan Wu; Cong Hu; Jiaojiao Guo; Qin Yang; Jiliang Xia; Yanjuan He; Gang An; Lugui Qiu; Xiangling Feng; Wen Zhou

doi:10.1111/bjh.18684

Proline promotes proliferation and drug resistance of multiple myeloma by downregulation of proline dehydrogenase

Br J Haematol. 2023 May;201(4):704-717. doi: 10.1111/bjh.18684. Epub 2023 Feb 8.

Authors

Jingyu Zhang^{1

2}, Fangming Shi^{1

2}, Xing Liu^{1

2}, Xuan Wu¹, Cong Hu^{1

2}, Jiaojiao Guo^{1

2}, Qin Yang³, Jiliang Xia⁴, Yanjuan He¹, Gang An⁵, Lugui Qiu⁵, Xiangling Feng^{1

6}, Wen Zhou^{1

2}

Affiliations

¹ Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Geriatric Disorders, Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.
² Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
³ Department of Hematology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical College, University of South China, Hengyang, Hunan, China.
⁵ State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
⁶ Xiangya School of Public Health, Central South University, Changsha, Hunan, China.

PMID: 36755409
DOI: 10.1111/bjh.18684

Abstract

Amino acids in the bone marrow microenvironment (BMME) are a critical factor for multiple myeloma (MM) progression. Here, we have determined that proline is elevated in BMME of MM patients and links to poor prognosis in MM. Moreover, exogenous proline regulates MM cell proliferation and drug resistance. Elevated proline in BMME is due to bone collagen degradation and abnormal expression of the key enzyme of proline catabolism, proline dehydrogenase (PRODH). PRODH is downregulated in MM patients, mainly as a result of promoter hypermethylation with high expression of DNMT3b. Thus, overexpression of PRODH suppresses cell proliferation and drug resistance of MM and exhibits therapeutic potential for treatment of MM. Altogether, we identify proline as a key metabolic regulator of MM, unveil PRODH governing MM progression and provide a promising therapeutic strategy for MM treatment.

Keywords: PRODH; drug resistance; multiple myeloma; proline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Proliferation
Down-Regulation
Drug Resistance
Humans
Multiple Myeloma* / drug therapy
Multiple Myeloma* / genetics
Proline / metabolism
Proline Oxidase / genetics
Proline Oxidase / metabolism
Tumor Microenvironment

Substances

Proline Oxidase
Proline