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

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.

Automated summary

Amino acids, particularly proline, in the bone marrow microenvironment (BMME) play a crucial role in multiple myeloma (MM) progression. Elevated proline levels in BMME are associated with poor prognosis in MM patients. The abnormal expression of proline dehydrogenase (PRODH), a key enzyme in proline catabolism, and bone collagen degradation contribute to the increased proline levels. PRODH downregulation in MM patients is mainly caused by promoter hypermethylation and overexpression of DNMT3b. Overexpression of PRODH suppresses MM cell proliferation and drug resistance, suggesting its potential as a therapeutic target for MM treatment.