title: KRAS NF-κB is involved in the development of zinc resistance and reduced curability in prostate cancer.
abstract: Zinc(II) ions are important components of many proteins and are involved in numerous cellular processes such as apoptosis or drug resistance. Prostate cancer has a unique relationship with zinc(II) ions. However, the relationship was examined only in short-term zinc(II) treatments. Therefore, the aim of this study was to create zinc-resistant prostatic cell lines at various stages of the disease (22Rv1 and PC-3) and a normal prostate epithelium (PNT1A) using a long-term zinc exposure. Consequently, the expression profile of the following genes was analyzed: BAX, Bcl-2, Beclin-1, CFLAR, HIF1α, KRAS, mTOR, MT1A, MT2A, NF-κB1, p53, survivin, ZIP1, ZnT-1. The resistance was verified using the MTT test; on average a 1.35-fold lower zinc(II) toxicity (higher IC50) was determined in zinc(II)-resistant cells. The associated resistance to cisplatin was also determined; IC50 for cisplatin was 1.52-fold higher. With regard to the gene expression profiles, our results indicate that differential mechanisms participate in the short-term zinc toxicity regulation and long-term resistance; the short-term treatment was associated with MT2A (p < 0.001), ZnT-1 (p < 0.001), and MT1A (p < 0.03) and the long-term resistance was associated particularly with NF-κB1 (p < 0.001), CFLAR (p < 0.001), KRAS (p < 0.001), p53 (p < 0.002), survivin (p = 0.02), ZIP1 (p = 0.002), BAX (p = 0.005), and HIF1α (p = 0.05). Therefore, the KRAS-PI3K-NF-κB pathway is expected to play a crucial role in the regulation of zinc resistance. In summary, compared to previous studies, identical mechanisms of resistance were demonstrated on multiple cell lines, both non-tumor and tumorous, derived both from primary and advanced secondary sites.
authors.affiliation: Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic. masarik@med.muni.cz.
authors.forename: Monika
authors.initials: M
authors.lastname: Holubova
authors.forename: Martina
authors.initials: M
authors.lastname: Axmanova
authors.forename: Jaromir
authors.initials: J
authors.lastname: Gumulec
authors.forename: Martina
authors.initials: M
authors.lastname: Raudenska
authors.forename: Marketa
authors.initials: M
authors.lastname: Sztalmachova
authors.forename: Petr
authors.initials: P
authors.lastname: Babula
authors.forename: Vojtech
authors.initials: V
authors.lastname: Adam
authors.forename: Rene
authors.initials: R
authors.lastname: Kizek
authors.forename: Michal
authors.initials: M
authors.lastname: Masarik
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy; D059467:Transcriptome; D015032:Zinc / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D016328:NF-kappa B; D058539:Phosphatidylinositol 3-Kinase; D015032:Zinc; D002945:Cisplatin