Deciphering The Role And Molecular Mechanism Of SIRT3 In Prostate Cancer Progression And Gentamicin Induced Hearing Loss Model

Although modern technology has brought higher medical condition to people,cancer and some diseases on nervous system are fatal.Scientists are committed to discover new methods to weaken harm caused by such diseases for quite some time.SIRT3,a member of Sirtuin family,is regarded as an important regulator involved in several kinds of age related diseases.For example,it is involved in the regulation of neurodegeneration,cardiovascular disease,hepatic steatosis,increased adiposity,cancer and so on.Here,with the assistance of different disease model,we unveiled the effect of SIRT3 in certain diseases and elucidated the underlying mechanism.Our results are expected to be the crucial part of novel strategy in clinical therapies in the future.Researchers devote themselves to figure out the relationship between SIRT3 and cancer for years.Unfortunately,it remains unclear how SIRT3 works in certain cancers,especially in prostate cancer.In part one,we found that SIRT3 was down-regulated in prostate carcinomas.Overexpression of SIRT3 curbed prostate cancer cell growth both in vitro and in vivo,whereas knockdown of SIRT3 raised prostate tumor cell growth.Mechanistically,the tumor suppression effect of SIRT3 was acquired via its inhibition of the PI3K/Akt pathway.Notably,upregulation of SIRT3 suppressed the activation of Akt,leading to the ubiquitination and degradation of oncoprotein c-MYC.Our results uncovered SIRT3's function and the underlying mechanism in prostate cancer,which might provide therapeutic implications for such disease.Researchers gradually realized that overexpressing SIRT3 with different methods might control even reverse certain diseases.Thus,it will be very potential to find novel SIRT3 stimulators.In part two,we reported that by using a acute stress-induced hair cell loss model in vitro,adjudin,a multi-functional small molecule drug,could up-regulate SIRT3 and protect mammalian cochlear hair cells from damage.The immunohistochemistry,western blotting and RT-PCR analyses revealed that adjudin performed its otoprotective effects by stimulating the level of SIRT3,which regulates reactive oxygen species(ROS)level in cochlear epithelial cells and quells the production of ROS and apoptotic cells induced by gentamicin.Besides,SIRT3 knock down experiments verified that SIRT3-ROS signaling axis mediated hair cell protection against gentamicin by adjudin.Furthermore,adjudin's otoprotection capabilities were also discovered in an in vivo hearing loss animal model.Taken together,these findings delineated adjudin as a novel otoprotective small molecule via up-regulating SIRT3 levels and SIRT3 may be of therapeutic value in hearing protection induce from acute stress.To sum up,we reported the first time that SIRT3 could be used as a prostate cancer suppressor,and also,we found a novel small molecule which could act as a SIRT3 activator.Our result provided new evidence of the effect of SIRT3 and its activator in clinical research in the future.