Allosteric Inhibitor Of Phosphoglycerol Mutanase 1 Not Only Suppresses Lung Adenocarcinoma But Also Overcomes Erlotinib Resistance

Phosphoglycerate mutase 1 is an important enzyme in the aerobic glycolysis pathway of tumor cells and catalyzes the conversion of 3-phosphoglycerate to2-phosphoglycerate,which not only regulates the rate of glycolysis,but also regulates concentration,participate in the regulation of pentose phosphate pathway and serine synthesis pathway,and thus affect the entire metabolic network.PGAM1 expression and activity abnormally elevated play an important role in the occurrence and development of a variety of tumors,is expected as an anti-tumor target,the development of its inhibitors has also become one of the hot spots of anti-tumor drugs.Lung cancer is the most frequently diagnosed cancer among all malignancies,with lung adenocarcinomas accounting for 40 % of lung cancers.Erlotinib and other epidermal growth factor receptor tyrosine kinase inhibitors targeted treatment of lung adenocarcinoma significant effect,but extremely resistant recurrence.In this study,we investigated the effect and mechanism of PGAM1 inhibitors on lung adenocarcinoma and its Erlotinib-resistant cells.First of all,through the statistical analysis of clinical data and we found that the abnormal expression of PGAM1 and lung adenocarcinoma prognosis was negatively correlated,suggesting that PGAM1 can be used as a target for the treatment of lung adenocarcinoma;cell experiments were screened and obtained high activity and specificity of PGAM1 The constitutive inhibitor HKB99 can significantly inhibit the proliferation and migration of lung adenocarcinoma cells,induce apoptosis and has little effect on normal bronchial epithelial cells with good selectivity.More experiments found that HKB99 can inhibit lung adenocarcinoma subcutaneous tumor growth and tail vein injection of tumor metastasis;what’s more,HKB99 combined with Erlotinib can synergistically inhibit lung adenocarcinoma tumor growth and overcome drug resistance;HKB99 can also repress the Erlotinib-resistance cells migration in vivo.To investigate the molecular mechanism,we found that HKB99 can restrain the interaction between PGAM1 and alpha smooth muscle actin,suggesting that HKB99 may have great influence on tumor cell motility by affecting the interaction between PGAM1 and ACTA2.The results of RNA-Seq and Western blot showed that HKB99 can inhibit the phosphorylation of mitogen-activated protein kinase and upregulate the phosphorylation of c-Jun,and knockdown of PGAM1 by sg RNA or si RNA also produced similar effects,suggesting that HKB99 can suppress the activity of MAPK signaling pathway after inhibiting PGAM1,thereby proinhibiting tumor cell proliferation and inducing apoptosis.In summary,the present study for the first time found that HKB99,an allosteric inhibitor of PGAM1,inhibits proliferation and tumor growth of lung adenocarcinoma,induces apoptosis,inhibits tumor metastasis,and overcomes Erlotinib.Clarified the molecular mechanism by which HKB99 affects cell motility through the interaction between PGAM1 and ACTA2 and then regulates cell proliferation and apoptosis by affecting MAPK signaling pathway.These results suggest that HKB99 is expected to be a new anti-tumor drug with high potency,low toxicity and anti-resistance.It can provide theoretical basis for the treatment of lung adenocarcinoma with PGAM1 inhibitor and Erlotinib,and has important clinical significance for individualized treatment of lung adenocarcinoma.