title: Ubenimex inhibits cell proliferation, migration and invasion by inhibiting the expression of APN and inducing autophagic cell death in prostate cancer cells.
abstract: Prostate cancer is the second most frequently diagnosed cancer in males worldwide and is commonly associated with metastasis. Moreover, in prostate cancer, aminopeptidase N (APN) expression is closely correlated with metastasis. Ubenimex, an APN inhibitor, is widely used as an adjunct therapy for cancer, enhancing the function of immunocompetent cells and conferring antitumor effects. However, due to the low expression of APN, it is rarely used to treat prostate cancer. Recently, the induction of autophagy as a molecular mechanism has been strongly connected with tumor cell death. Thus, we investigated whether ubenimex could inhibit cell proliferation, migration and invasion by downregulating APN expression to induce autophagic cell death in prostate cancer cells. The LNCaP and PC-3 cell lines were treated with different doses of ubenimex. Cell viability was measured using growth curve analysis and WST-8 proliferation assay. Autophagic cell death was assessed using fluorescence microscopy and acridine orange/ethidium bromide (AO/EB) staining. Protein expression was assessed by immunofluorescence and western blot analyses. Autophagosomes were evaluated using transmission electron microscopy. Wound-healing migration assays were performed to determine the migratory ability of the PC-3 cells. In addition, nude mice were used in the present study to examine PC-3 cell proliferation in vivo. The results revealed that APN expression differed between the metastatic and non-metastatic prostate cancer cells. In addition, ubenimex inhibited APN expression in the prostate cancer cells. Ubenimex increased prostate cancer cell death, as determined using the lactate dehydrogenase (LDH) cytotoxicity assay. This effect was accompanied by increased levels of LC3B. Furthermore, ubenimex inhibited PC-3 cell proliferation in vivo and in vitro. Ubenimex inhibited the cell migration and invasion in prostate cancer cells by downregulating APN expression. Finally, ubenimex induced autophagic cell death in both metastatic and non-metastatic prostate cancer cells. Based on these results, ubenimex appears to be an excellent adjunctive therapy for the treatment of prostate cancer.
authors: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors: Xiaoqing
authors: X
authors: Wang
authors: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors: Zhihong
authors: Z
authors: Niu
authors: Shandong University, Jinan, Shandong 250000, P.R. China.
authors: Yang
authors: Y
authors: Jia
authors: Shandong University, Jinan, Shandong 250000, P.R. China.
authors: Meng
authors: M
authors: Cui
authors: Department of Neurology, Shandong Police Hospital, Jinan, Shandong 250000, P.R. China.
authors: Liping
authors: L
authors: Han
authors: Department of Dermatology, Mount Qianfu Attached Hospital of Shandong University, Jinan, Shandong 250000, P.R. China.
authors: Yongfei
authors: Y
authors: Zhang
authors: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors: Zheng
authors: Z
authors: Liu
authors: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors: Dongbin
authors: D
authors: Bi
authors: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.
authors: Shuai
authors: S
authors: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001343:Autophagy; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex