| Prostate cancer is one of the most common cancers occur in genitourinary system,and the second leading cause of death among male cancer patients in the United States,with a rising prevalence in China.Radiotherapy and hormone therapy are commonly served as primary treatments for prostate cancer except operation.However,a considerable proportion of patients respond poorly to both therapies and then progress to metastatic disease.Therefore,more novel and effective targeted therapies are greatly in high demand.Genetic alterations in the phosphoinositide 3-kinase(PI3K)/AKT/ mammalian target of rapamycin(m TOR)pathway frequently occur in prostate cancer,which mediates cell growth,proliferation,survival and autophagy,thus regulating tumor maintenance and progression.DEPTOR,a common component found in both the m TORC1 and m TORC2 complexes,directly binds to m TOR to block the activities of both complexes.However,DEPTOR has been shown to play a context dependent role in the regulation of proliferation and the survival of various cancer cells in cell culture settings.The in vivo role of DEPTOR in tumorigenesis remains elusive.In this study,by using immunohistochemistry,we detected the DEPTOR expression in human prostate cancer tissues,in combination with the data obtained from TCGA database to determine the m RNA level of DEPTOR.Moreover,the correlation between the DEPTOR expression and clinical and pathological data from prostate cancer patients was analyzed.Then we generated DEPTOR knockout,knockdown and overexpression prostate cancer cells to investigate the role of DEPTOR as oncogene or tumor suppressor.Immunoblotting and drugs treatment were utilized to investigate the underlying molecular mechanisms.At last,the suppressive role of DEPTOR in prostate cancer progression was further confirmed directly and strongly using a Deptor-knockout(KO)mouse model,in combination with a heterozygous Pten deletion to trigger tumorigenesis.According to the above experiments,we first showed that the levels of both DEPTOR protein and m RNA were substantially decreased in human prostate cancer tissues,which positively correlated with disease progression.DEPTOR depletion accelerated proliferation and survival,migration,and invasion in human prostate cancer cells.Mechanistically,DEPTOR depletion not only activated both m TORC1 and m TORC2 signals to promote cell proliferation and survival,but also induced an AKTdependent epithelial–mesenchymal transition(EMT)via the induction of Snail and β-catenin nuclear translocation to promote cell migration and invasion.Abrogation of m TOR or AKT activation rescued the biological consequences of DEPTOR depletion.Importantly,in a Deptor-KO mouse model,Deptor knockout accelerated prostate tumorigenesis triggered by Pten loss via the activation of m TOR signaling.Collectively,our study demonstrates that DEPTOR is a tumor suppressor in the prostate,and its depletion promotes tumorigenesis via the activation of m TORC1 and m TORC2 signals.Thus,DEPTOR reactivation via small molecule compounds or other means targeting its degradation would have therapeutic potential for the treatment of prostate cancer. |
