Study On The Anti-breast Cancer Effect And Its Mechanism Of Marine Natural Product Coibamide A

Natural products are useful tools for the research of biological mechanisms and drug discovery.According to rough calculations,as of 2008,about 80% of the small molecule anti-cancer drugs newly marketed worldwide were originated from natural products or their analogs.Therefore,the development of anti-tumor drugs with natural products as lead compounds has great application potential.In recent years,a variety of depsipeptides with significant anti-tumor activity have been isolated from marine organisms,providing new sources and approaches for the research and development of anti-tumor drugs.Coibamide A(CA)is a highly N-methyl stable depsipeptide derived from marine cyanobacterium.It has been considered as a promising lead compound for cancer treatment due to its excellent tumor cell growth inhibitory properties and sub-nanomolar potency.However,the specific inhibitory effect and molecular mechanism of CA on cancer cells remain unclear.This paper mainly studies the anti-breast cancer effect of marine natural product CA and its underlying molecular mechanism of action,explores its potential as a clinical anti-cancer drug in the future,and provides theoretical and experimental basis for the development of relevant anti-cancer drugs.Here,we demonstrated that CA treatment induced caspase-independent cell death in breast cancer cells through western blot and other methods.Immunofluorescence staining and other methods showed that CA treatment also resulted in severe lysosome defects,which was attributed to the impaired glycosylation of lysosome membrane proteins LAMP1 and LAMP2.As a result,autophagosome-lysosome fusion was blocked upon CA treatment,leading to failure of autophagosomes clearance.Furthermore,we provided evidence that this autophagy defect partially led to the CA-induced tumor cell death.At the same time,we also used bioinformatics and other methods to detect the cancer cell signaling pathways affected by CA,and investigated the tumor inhibition effect of CA in combination with existing clinical drugs mTORC1 inhibitor(Rapamycin or Everolimus)in vivo and in vitro.Our results demonstrated that CA regulated PI3K-AKT signaling pathway in breast cancer cells by specifically inhibiting mTORC2 instead of mTORC1,and CA combined with Rapamycin or Everolimus had significant tumor inhibition effects in vivo and in vitro.In a word,our work reveals a novel mechanism of the anti-cancer effect of CA,which will promote the further application of CA in cancer therapy.