The 60-kDa heat shock protein regulates energy rearrangement and protein synthesis to promote proliferation of multiple myeloma cells.
To investigate the cellular mechanisms of multiple myeloma (MM), we used liquid chromatography-tandem mass spectrometry for proteomics analysis of CD138+ plasma cells from patients with MM and healthy controls. We found that the 60-kDa heat shock protein (HSP60, also known as HSPD1) was significantly upregulated in myeloma cells. HSP60 is an important chaperone protein that regulates the homeostasis of mitochondrial proteins and maintains mitochondrial function. Knockdown (KD) of HSP60 in myeloma cells resulted in inhibition of proliferation and reduced the quality of the mitochondria. Mitochondrial stress tests showed that HSP60 KD inhibited glycolysis and mitochondrial activity. Metabolomics showed a decrease in glycolysis and tricarboxylic acid cycle metabolites, and inhibited the formation of creatine and phosphocreatine by the reaction of S-adenosylmethionine (SAM) with amino acids mediated by demethyladenosine transferase 1, mitochondrial (TFB1M) and reduced energy storage substances. Moreover, HSP60 silencing influenced the synthesis of ribonucleotides and nicotinamide adenine dinucleotide phosphate (NADPH) by the pentose phosphate pathway to inhibit cell proliferation. HSP60 KD inhibited 5' adenosine monophosphate-activated protein kinase (AMPK), which inhibited the key enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), effecting the metabolism of fatty acids by inhibiting malonyl-coenzyme A. Our data suggest that reduced HSP60 expression alters metabolic reprogramming in MM, inhibits tumour progression and reduces mitochondrial-dependent biosynthesis, suggesting that HSP60 is a potential therapeutic target for MM treatment.
['Wu|Xiaoxiao|X|', 'Guo|Jianying|J|', 'Chen|Yuling|Y|', 'Liu|Xiaohui|X|', 'Yang|Guangzhong|G|', 'Wu|Yin|Y|', 'Tian|Ying|Y|', 'Liu|Nian|N|', 'Yang|Lin|L|', 'Wei|Songren|S|', 'Deng|Haiteng|H|', 'Chen|Wenming|W|0000-0001-6298-8489']
D045744:Cell Line, Tumor D049109:Cell Proliferation D018834:Chaperonin 60 D004734:Energy Metabolism D055785:Gene Knockdown Techniques D006801:Humans D024101:Mitochondrial Proteins D009101:Multiple Myeloma D009363:Neoplasm Proteins D014176:Protein Biosynthesis
multiple myeloma proteomics HSP60 metabolomics adenosine monophosphate-activated protein kinase (AMPK)