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@article{1199029,
author = {Holubová, Monika and Axmanová, Martina and Gumulec, Jaromír and Raudenská, Martina and Sztalmachová, Markéta and Babula, Petr and Adam, Vojtěch and Kizek, René and Masařík, Michal},
article_location = {Cambridge},
article_number = {7},
doi = {http://dx.doi.org/10.1039/c4mt00065j},
keywords = {CITRATE METABOLISM; EPITHELIAL-CELLS; CARCINOMA-CELLS; DNA-DAMAGE; T-ANTIGEN; EXPRESSION; METALLOTHIONEIN; TRANSPORTER; APOPTOSIS; GENES},
language = {eng},
issn = {1756-5901},
journal = {Metallomics},
title = {KRAS NF-kappa B is involved in the development of zinc resistance and reduced curability in prostate cancer},
volume = {6},
year = {2014}
}
TY - JOUR
ID - 1199029
AU - Holubová, Monika - Axmanová, Martina - Gumulec, Jaromír - Raudenská, Martina - Sztalmachová, Markéta - Babula, Petr - Adam, Vojtěch - Kizek, René - Masařík, Michal
PY - 2014
TI - KRAS NF-kappa B is involved in the development of zinc resistance and reduced curability in prostate cancer
JF - Metallomics
VL - 6
IS - 7
SP - 1240-1253
EP - 1240-1253
PB - Royal Society of Chemistry
SN - 17565901
KW - CITRATE METABOLISM
KW - EPITHELIAL-CELLS
KW - CARCINOMA-CELLS
KW - DNA-DAMAGE
KW - T-ANTIGEN
KW - EXPRESSION
KW - METALLOTHIONEIN
KW - TRANSPORTER
KW - APOPTOSIS
KW - GENES
N2 - 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.
ER -
HOLUBOVÁ, Monika, Martina AXMANOVÁ, Jaromír GUMULEC, Martina RAUDENSKÁ, Markéta SZTALMACHOVÁ, Petr BABULA, Vojtěch ADAM, René KIZEK and Michal MASAŘÍK. KRAS NF-kappa B is involved in the development of zinc resistance and reduced curability in prostate cancer. \textit{Metallomics}. Cambridge: Royal Society of Chemistry, 2014, vol.~6, No~7, p.~1240-1253. ISSN~1756-5901. Available from: https://dx.doi.org/10.1039/c4mt00065j.
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