Study Of Metformin Induced Chaperone Mediated Autophagy

Chaperone mediated autophagy(CMA)is a selective autophagy responsible for shipping soluble cytosolic proteins to lysosomes for degradation.Substrates of CMA contain KFERQ-like motif,which is recognized by HSC70 and assists HSC70 to deliver the substrates to lysosomes.CMA plays an important role in cellular quality control and cellular stress response.Recent studies of CMA suggested that CMA plays critical role in the developments of many diseases,such as cancer,obesity,aging,and neurodegeneration diseases.For example,CMA was found be able to suppress the proliferation and development of tumors by regulating glucose metabolism.Hexokinase Ⅱ(HK2)is a key enzyme involved in catalyzing the first committed step of glucose metabolism.HK2 has been recognized as an oncogenic kinase,which is required for initiation and maintenance of many tumors.In our previous study,HK2 has been demonstrated as a new substrate protein of CMA.Although the activation of CMA can reduce the levels of HK2 and suppress tumors,there is no suitable drugable compounds which can enhance the activity of CMA.In order to find novel drugable compounds which can induce CMA activity,we set up a cell-based HTS model.We made a cell line stably and evenly expressing HK2-EGFP,we named it HK2SSA1.We screened about 2000 compounds,and we chose metformin for further study from the hit compounds which can significantly reduce the level of HK2.Metformin is a classic biguanide hypoglycemic drug.Metformin is one of the most widely used oral antidiabetic drugs all over the world and it is remarkably secure.Plenty of epidemiological and experimental studies suggest that metformin has an anti-tumor effect through insulin dependent or non-dependent pathways.In this way,metformin is recognized as a potential anti-cancer drug candidate with important clinical value.Our experiments suggested that metformin can suppress tumors by inducing CMA and by reducing oncogenic proteins.Besides,we found that metformin may reduce the levels of p300 protein,and may inhibit the replication of hepatitis B virus(HBV).This suggested a novel perspective and scientific evidence for developing new anti-HBV therapy.