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

J 2014

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

HOLUBOVÁ, Monika, Martina AXMANOVÁ, Jaromír GUMULEC, Martina RAUDENSKÁ, Markéta SZTALMACHOVÁ et. al.

Basic information

Original name

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

Authors

HOLUBOVÁ, Monika (203 Czech Republic, belonging to the institution), Martina AXMANOVÁ (203 Czech Republic, belonging to the institution), Jaromír GUMULEC (203 Czech Republic, belonging to the institution), Martina RAUDENSKÁ (203 Czech Republic, belonging to the institution), Markéta SZTALMACHOVÁ (203 Czech Republic, belonging to the institution), Petr BABULA (203 Czech Republic), Vojtěch ADAM (203 Czech Republic), René KIZEK (203 Czech Republic) and Michal MASAŘÍK (203 Czech Republic, guarantor, belonging to the institution)

Edition

Metallomics, Cambridge, Royal Society of Chemistry, 2014, 1756-5901

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10600 1.6 Biological sciences

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 3.585

RIV identification code

RIV/00216224:14110/14:00076568

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1039/c4mt00065j

UT WoS

000338638000009

Keywords in English

CITRATE METABOLISM; EPITHELIAL-CELLS; CARCINOMA-CELLS; DNA-DAMAGE; T-ANTIGEN; EXPRESSION; METALLOTHIONEIN; TRANSPORTER; APOPTOSIS; GENES

Abstract

V originále

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.

Links

MUNI/A/1003/2013, interní kód MU

Name: Molekulární patofyziologie vybraných komplexních nemocí

Investor: Masaryk University, Category A

Citovat

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. 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.

@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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