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

Author(s)

Nascimento, Augusto S. ^[1] ; Peres, Luisa L. ^[2] ; Fari, Alessandra V. S. ^[2] ; Milani, Renato ^[2] ; Silva, Rodrigo A. ^[1] ; Fernandes, Jr., Celio da Costa ^[1] ; Peppelenbosch, Maikel P. ^[3] ; Ferreira-Halder, Carmen V. ^[2] ; Zambuzzi, Willian F. ^[1]

Affiliation

^[1] UNESP, Biosci Inst, Dept Chem & Biochem, Bioassays & Cell Dynam Lab, Botucatu, SP - Brazil

^[2] Univ Estadual Campinas, Biol Inst, Dept Biochem & Tissue Biol, OncoBiomarkers Res Lab, Campinas, SP - Brazil

^[3] Univ Med Ctr, Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdams Gravendijkwal 230, NL-3015 CE Rotterdam - Netherlands

• Document type: Journal article
• Source: ONCOTARGET; v. 8, n. 70, p. 114756-114768, DEC 29 2017.
• Web of Science Citations: 6

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. (AU)

• FAPESP's process: 14/22689-3 - Microvesicle/proteins-mediated paracrine signaling among bone and endothelial cells during bone development and regeneration
• Grantee: Willian Fernando Zambuzzi
• Support Opportunities: Research Grants - Young Investigators Grants