p73-dependent induction of 14-3-3sigma increases the chemo-sensitivity of drug-resistant human breast cancers.
It has been well documented that tumor suppressor p53 is mutated in about 50% of all human tumors. p53 status might be one of the critical determinants for the chemo-sensitivity of human tumors. In the present study, we have found that p53 family member p73 as well as 14-3-3sigma is down-regulated in response to adriamycin (ADR) in ADR-resistant human breast cancer-derived MBA-MD-436 cells which carry p53 mutation. Like p53, 14-3-3sigma was transactivated by p73 and, in turn, stabilized p73. Luciferase reporter analysis and colony formation assays demonstrated that 14-3-3sigma has an ability to enhance the p73-mediated transcriptional activity as well as its pro-apoptotic function. Furthermore, enforced expression of 14-3-3sigma increased the ADR sensitivity of MBA-MD-436 cells. Taken together, our present results strongly suggest that p73-dependent induction of 14-3-3sigma plays an important role in the regulation of chemo-sensitivity of breast cancers bearing p53 mutation.
Sang
Meixiang
M
Division of Biochemistry, Chiba Cancer Center Research Institute, Japan.
Li
Yuanyuan
Y
Ozaki
Toshinori
T
Ono
Sayaka
S
Ando
Kiyohiro
K
Yamamoto
Hideki
H
Koda
Tadayuki
T
Geng
Cuizhi
C
Nakagawara
Akira
A
D048948:14-3-3 Proteins; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm; D005092:Exonucleases; D005095:Exoribonucleases; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D048948:14-3-3 Proteins; D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human