14-3-3sigma-dependent resistance to cisplatin.
BACKGROUND
A major factor that impedes the clinical success of cisplatin-based chemotherapy for cancer is cisplatin resistance by cancer cells.


METHODS
The sensitivity of parental HCT116 human colon cancer cell line and its isogenic gene-knockout sub-lines to cisplatin was determined by clonogenicity assay; furthermore, p53 activation, p21 expression, cell cycle arrest and senescence in these cells after cisplatin treatment were investigated.


RESULTS
Parental cells were six times more resistant than 14-3-3sigma-knockout (sigma-KO) cells to cisplatin. Moreover, activation of p53, p53-dependent expression of p21 and p21-dependent senescence were observed in sigma-KO, but not parental cells after a treatment with a low cisplatin dose.


CONCLUSIONS
A 14-3-3sigma-dependent mechanism inhibits p53 activation in parental cells treated with a low cisplatin dose, thereby blocking p21 expression that is essential for senescence and consequently conferring to the parental cells a significant degree of resistance to cisplatin.
Han
Zhiyong
Z
Department of Preclinical Sciences, New York College of Podiatric Medicine, New York, NY 10035, U.S.A. zhan@nycpm.edu
Dimas
Konstantinos
K
Tian
Xuefei
X
Wang
Yongbao
Y
Hemmi
Hiromichi
H
Yamada
Kanae
K
Kato
Naoyuki
N
Pantazis
Panayotis
P
Ramanujam
Rama J
RJ
Anant
Shrikant
S
Wyche
James H
JH
Houchen
Courtney W
CW
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D016922:Cellular Senescence / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D002945:Cisplatin