title: Acquired resistance to HSP90 inhibitor 17-AAG and increased metastatic potential are associated with MUC1 expression in colon carcinoma cells.
abstract: Heat shock protein 90 (HSP90) is a molecular chaperone required for the stability and function of many proteins. The chaperoning of oncoproteins by HSP90 enhances the survival, growth, and invasive potential of cancer cells. HSP90 inhibitors are promising new anticancer agents, in which the benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is currently in clinical evaluation. However, the implications of acquired resistance to this class of drug remain largely unexplored. In the present study, we have generated isogenic human colon cancer cell lines that are resistant to 17-AAG by continued culturing in the compound. Cross-resistance was found with another HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin. The resistant cells showed obvious morphology changes with a metastatic phenotype and significant increases in migration and adhesion to collagens. Western blotting analysis of epithelial-mesenchymal transition molecular markers found that expression of E-cadherin downregulated, whereas expression of N-cadherin and β-catenin upregulated in the resistant cells. Mucin 1 (MUC1) has been reported to mediate metastasis as well as chemical resistance in many cancers. Here, we found that MUC1 expression was significantly elevated in the acquired drug resistance cells. 17-AAG treatment could decrease MUC1 more in parental cells than in acquired 17-AAG-resistant cells. Further study found that knockdown of MUC1 expression by small interfering RNA could obviously re-sensitize the resistant cells to 17-AAG treatment, and decrease the cell migration and adhesion. These were coupled with a downregulation in N-cadherin and β-catenin. The results indicate that HSP90 inhibitor therapies in colon carcinomas could generate resistance and increase metastatic potential that might mediated by upregulation of MUC1 expression. Findings from this study further our understanding of the potential clinical effects of HSP90-directed therapies in colon carcinomas.
authors.affiliation: aDepartment of Colorectal Surgery, Tumor Institute of Yunnan Province, the Third Affiliated Hospital of Kunming Medical University bDepartment of Pharmacy, the Second Affiliated Hospital of Kunming Medical University cDepartment of Medical Imaging, the First Affiliated Hospital of Kunming Medical University, Kunming, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Ban
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.forename: Zhi-Yao
authors.initials: ZY
authors.lastname: Li
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
authors.forename: Yong-Chun
authors.initials: YC
authors.lastname: Zhou
authors.forename: Xi-Cai
authors.initials: XC
authors.lastname: Wang
authors.forename: Cong-Guo
authors.initials: CG
authors.lastname: Jin
authors.forename: Jia-Gui
authors.initials: JG
authors.lastname: Ye
authors.forename: Ding-Ding
authors.initials: DD
authors.lastname: Ma
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.forename: You-Guang
authors.initials: YG
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D055786:Gene Knockout Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D034622:RNA Interference
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C060192:MUC1 protein, human; D018396:Mucin-1; C112765:tanespimycin