Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated TP53 and MDM2 up-regulation
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Zuzanna Tracz-Gaszewska1,2, Marta Klimczak1,3, Przemyslaw Biecek4,5, Marcin Herok1,6, Marcin Kosinski5,4, Maciej B. Olszewski1, Patrycja Czerwińska1,7, Milena Wiech1, Maciej Wiznerowicz7, Alicja Zylicz1, Maciej Zylicz1 and Bartosz Wawrzynow2
1International Institute of Molecular and Cell Biology, Warsaw, Poland
2Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland
3Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
4Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, Warsaw, Poland
5Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
6Nencki Institute of Experimental Biology, PAS, Warsaw, Poland
7Laboratory of Gene Therapy, Department of Cancer Immunology, The Greater Poland Cancer Center, Poznan, Poland
Bartosz Wawrzynow, email: [email protected]
Maciej Zylicz, email: [email protected]
Keywords: apoptosis, heat shock protein (HSP), mutant p53 gain-of-function, mouse double minute 2 homolog (MDM2), p73 tumor suppressor
Received: August 01, 2016 Accepted: June 13, 2017 Published: June 30, 2017
Utilizing the TCGA PANCAN12 dataset we discovered that cancer patients with mutations in TP53 tumor suppressor and overexpression of MDM2 oncogene exhibited decreased survival post treatment. Interestingly, in the case of breast cancer patients, this phenomenon correlated with high expression level of several molecular chaperones belonging to the HSPA, DNAJB and HSPC families. To verify the hypothesis that such a genetic background may promote chaperone-mediated chemoresistance, we employed breast and lung cancer cell lines that constitutively overexpressed heat shock proteins and have shown that HSPA1A/HSP70 and DNAJB1/HSP40 facilitated the binding of mutated p53 to the TAp73α protein. This chaperone-mediated mutated p53–TAp73α complex induced chemoresistance to DNA damaging reagents, like Cisplatin, Doxorubicin, Etoposide or Camptothecin. Importantly, when the MDM2 oncogene was overexpressed, heat shock proteins were displaced and a stable multiprotein complex comprising of mutated p53-TAp73α-MDM2 was formed, additionally amplifying cancer cells chemoresistance. Our findings demonstrate that molecular chaperones aid cancer cells in surviving the cytotoxic effect of chemotherapeutics and may have therapeutic implications.
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