Oncotarget

Research Papers:

Phosphoproteome profiling reveals critical role of JAK-STAT signaling in maintaining chemoresistance in breast cancer

Augusto S. Nascimento, Luisa L. Peres, Alessandra V.S. Fari, Renato Milani, Rodrigo A. Silva, Celio Jr. da Costa Fernandes, Maikel P. Peppelenbosch, Carmen V. Ferreira-Halder and Willian F. Zambuzzi _

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Oncotarget. 2017; 8:114756-114768. https://doi.org/10.18632/oncotarget.21801

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Abstract

Augusto S. Nascimento1,*, Luisa L. Peres2,*, Alessandra V.S. Fari2, Renato Milani2, Rodrigo A. Silva1, Celio Jr. da Costa Fernandes1, Maikel P. Peppelenbosch3, Carmen V. Ferreira-Halder2 and Willian F. Zambuzzi1

1Bioassays and Cell Dynamics Laboratory, Department of Chemistry and Biochemistry, Bioscience Institute, UNESP, Botucatu, Sao Paulo, Brazil

2OncoBiomarkers Research Laboratory, Department of Biochemistry and Tissue Biology, Biology Institute, UNICAMP, Campinas, Sao Paulo, Brazil

3Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam’s Gravendijkwal 230, NL-3015 CE Rotterdam, The Netherlands

*These authors have contributed equally on this work

Correspondence to:

Willian F. Zambuzzi, email: wzambuzzi@ibb.unesp.br

Keywords: breast cancer, chemoresistance, phosphoproteome, kinase, JAK

Received: October 24, 2016     Accepted: September 13, 2017     Published: October 10, 2017

ABSTRACT

Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MCF7Res cells to chemotherapy-sensitive MCF cells using a peptide array approach that provides an atlas of cellular kinase activities and consequently, predominant pathways can be identified. We observed that peptides phosphorylated by elements of JAK-STAT signaling pathway and PKC signaling pathways are subject to extensive kinase activity in MCF7Res cells as compared to chemotherapy-sensitive MCF cells; and Western blotting confirmed relatively strong activation of these signaling pathways in chemoresistant cells. Importantly, treatment of cells with Tofacitinib, a FDA-approved JAK inhibitor, converted chemoresistant cells to chemosensitive cells, inducing apoptosis when used in conjunction with doxorubicin. Thus our results reveal that chemoresistance in breast cancer is associated with activation of JAK/STAT signaling and suggest that JAK2 may be useful for combating chemoresistance in breast cancer.


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