Oncotarget

Research Papers:

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

Zuzanna Tracz-Gaszewska, Marta Klimczak, Przemyslaw Biecek, Marcin Herok, Marcin Kosinski, Maciej B. Olszewski, Patrycja Czerwińska, Milena Wiech, Maciej Wiznerowicz, Alicja Zylicz, Maciej Zylicz and Bartosz Wawrzynow _

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Oncotarget. 2017; 8:82123-82143. https://doi.org/10.18632/oncotarget.18899

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Abstract

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

Correspondence to:

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

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.


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