Amino acid metabolic remodeling is a hallmark of cancer,driving an increased nutritional demand for amino acids.Amino acids are pivotal for energetic regulation,biosynthetic support,and ho-meostatic maintenance to stimulate cancer progression.However,the role of phenylalanine in multiple myeloma(MM)remains unknown.Here,we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow(BM)cells.After the treatment,phenylalanine levels increase in plasma and decrease in BM.This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM pro-gression.The requirement for phenylalanine by MM cells exhibits a similar pattern.Inhibiting phenylal-anine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib(BTZ)treatment in vitro and murine models.Mechanistically,phenylalanine deprivation induces excessive endo-plasmic reticulum stress and leads to MM cell apoptosis through the ATF3-CHOP-DR5 pathway.Inter-ference with ATF3 significantly affects phenylalanine deprivation therapy.In conclusion,we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling.Phenylal-anine is necessary for MM proliferation,and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.
Institute of Clinical Medical Sciences,China-Japan Friendship Hospital,Capital Medical University Beijing 100029,China
Department of Pharmacy,China-Japan Friendship Hospital,Beijing 100029,China
Beijing Chao-Yang Hospital,Capital Medical University,Beijing 100020,China
Institute of Chemicals Safety,Chinese Academy of Inspection and Quarantine,Beijing 100020,China
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Capital,s Funds for Health Improvement and Research(CFH),ChinaCapital,s Funds for Health Improvement and Research(CFH),ChinaState Key Laboratory of Respiratory Health and Multimorbidity
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