Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis  

作　　者：Longhao Cheng Xiaoxue Wang Aijun Liu Ying Zhu Hu Cheng Jiangling Yu Lili Gong Honglin Liu Guolin Shen Lihong Liu 

机构地区：[1]Institute of Clinical Medical Sciences,ChinaeJapan Friendship Hospital,Capital Medical University,Beijing 100029,China [2]Department of Pharmacy,ChinaeJapan Friendship Hospital,Beijing 100029,China [3]Beijing Chao-Yang Hospital,Capital Medical University,Beijing 100020,China [4]Institute of Chemicals Safety,Chinese Academy of Inspection and Quarantine,Beijing 100020,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3493-3512,共20页药学学报（英文版）

基　　金：supported by the Capital’s Funds for Health Improvement and Research(CFH)(Nos.2020-1-2031 and 2020-2-4082,China);State Key Laboratory of Respiratory Health and Multimorbidity.

摘　　要：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 homeostatic 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 progression.The requirement for phenylalanine by MM cells exhibits a similar pattern.Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib(BTZ)treatment in vitro and murine models.Mechanistically,phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3eCHOPeDR5 pathway.Interference with ATF3 significantly affects phenylalanine deprivation therapy.In conclusion,we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling.Phenylalanine is necessary for MM proliferation,and its aberrant demand highlights the importance of lowphenylalanine diets as an adjuvant treatment for MM.

关 键 词：Multiple myeloma PHENYLALANINE Amino acid metabolism Nutrient deprivation Cancer therapy Endoplasmic reticulum stress ATF3 Apoptosis 

分 类 号：R733.3[医药卫生—肿瘤]