title: Wnt pathway activation and ABCB1 expression account for attenuation of proteasome inhibitor-mediated apoptosis in multidrug-resistant cancer cells.
abstract: Multiple drug resistance (MDR) is a major obstacle to attenuating the effectiveness of chemotherapy to many human malignancies. Proteasome inhibition induces apoptosis in a variety of cancer cells and is recognized as a novel anticancer therapy approach. Despite its success, some multiple myeloma patients are resistant or become refractory to ongoing treatment by bortezomib suggesting that chemoresistant cancer cells may have developed a novel mechanism directed against the proteasome inhibitor. The present study aimed to investigate potential mechanism(s) of attenuation in a MDR cell line, MES-SA/Dx5. We found that compared to the parental human uterus sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the ABCB1 was more resistant to MG132 and bortezomib, escaping the proteasome inhibitor-induced apoptosis pathway. The resistance was reversed by co-treatment of MG132 and the ABCB1 inhibitor verapamil. The data indicated that ABCB1 might play a role in the efflux of MG132 from the MES-SA/Dx5 cells to reduce MG132-induced apoptosis. Furthermore, the canonical Wnt pathway was found activated only in the MES-SA/Dx5 cells through active β-catenin and related transactivation activities. Western blot analysis demonstrated that Wnt-targeting genes, including c-Myc and cyclin D1, were upregulated and were relevant in inhibiting the expression of p21 in MES-SA/Dx5 cells. On the other hand, MES-SA cells expressed high levels of p21 and downregulated cyclin D1 and caused cell cycle arrest. Together, our study demonstrated the existence and participation of ABCB1 and the Wnt pathway in an MDR cell line that attenuated proteasome inhibitor-induced apoptosis.
authors.affiliation: a Department of Medical Biotechnology and Laboratory Science; College of Medicine ; Chang Gung University ; Tao-Yuan , Taiwan , Republic of China.
authors.forename: Kowit Yu
authors.initials: KY
authors.lastname: Chong
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Hsu
authors.forename: Tsai-Hsien
authors.initials: TH
authors.lastname: Hung
authors.forename: Han-Shu
authors.initials: HS
authors.lastname: Hu
authors.forename: Tsung-Teng
authors.initials: TT
authors.lastname: Huang
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Wang
authors.forename: Chihuei
authors.initials: C
authors.lastname: Wang
authors.forename: Chuan-Mu
authors.initials: CM
authors.lastname: Chen
authors.forename: Kong Bung
authors.initials: KB
authors.lastname: Choo
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Tseng
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D008954:Models, Biological; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D060449:Wnt Signaling Pathway
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D061988:Proteasome Inhibitors
keywords: Wnt; apoptosis; cancer; cell cycle; multiple drug resistance; proteasome inhibitor