Publication details

KRAS NF-kappa B is involved in the development of zinc resistance and reduced curability in prostate cancer

Authors

HOLUBOVÁ Monika AXMANOVÁ Martina GUMULEC Jaromír RAUDENSKÁ Martina SZTALMACHOVÁ Markéta BABULA Petr ADAM Vojtěch KIZEK René MASAŘÍK Michal

Year of publication 2014
Type Article in Periodical
Magazine / Source Metallomics
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1039/c4mt00065j
Field Biochemistry
Keywords CITRATE METABOLISM; EPITHELIAL-CELLS; CARCINOMA-CELLS; DNA-DAMAGE; T-ANTIGEN; EXPRESSION; METALLOTHIONEIN; TRANSPORTER; APOPTOSIS; GENES
Description 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, HIF1 alpha, KRAS, mTOR, MT1A, MT2A, NF-kappa B1, 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-kappa B1 (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 HIF1 alpha (p = 0.05). Therefore, the KRAS-PI3K-NF-kappa B 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.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info