Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated TP53 and MDM2 up-regulation

// Zuzanna Tracz-Gaszewska 1, 2 , Marta Klimczak 1, 3 , Przemyslaw Biecek 4, 5 , Marcin Herok 1, 6 , Marcin Kosinski 5, 4 , Maciej B. Olszewski 1 , Patrycja Czerwinska 1, 7 , Milena Wiech 1 , Maciej Wiznerowicz 7 , Alicja Zylicz 1 , Maciej Zylicz 1 and Bartosz Wawrzynow 2 1 International Institute of Molecular and Cell Biology, Warsaw, Poland 2 Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland 3 Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland 4 Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, Warsaw, Poland 5 Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland 6 Nencki Institute of Experimental Biology, PAS, Warsaw, Poland 7 Laboratory of Gene Therapy, Department of Cancer Immunology, The Greater Poland Cancer Center, Poznan, Poland Correspondence to: Bartosz Wawrzynow, email: bwawrzynow@iimcb.gov.pl Maciej Zylicz, email: mzylicz@iimcb.gov.pl 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 ABSTRACT 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.