Phosphorylated Hsp27 promotes adriamycin resistance in breast cancer cells through regulating dual phosphorylation of c-Myc

• Published in: Cellular signalling 2023-12, Vol.112, p.110913-110913, Article 110913
• Main Authors: Bi, Xiaowen, Zhang, Miao, Zhou, Jinyi, Yan, Xintong, Cheng, Lixia, Luo, Lan, Huang, Chunhong, Yin, Zhimin
• Format: Article
• Language: English
• Subjects: Adriamycin resistance; Apoptosis; Breast Neoplasms - metabolism; c-Myc; Doxorubicin - pharmacology; Female; Heat shock protein 27; HSP27 Heat-Shock Proteins - metabolism; Humans; Phosphorylation; Protein phosphatase 2A
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2023.110913

Chemotherapy resistance of breast cancer cells is one of the major factors affecting patient survival rate. Heat shock protein 27 (Hsp27) is a member of the small heat shock protein family that has been reported to be associated with chemotherapy resistance in tumor cells, but the exact mechanism is not fully understood. Here, we explored the regulation of Hsp27 in adriamycin-resistant pathological conditions of breast cancer in vitro and in vivo. We found that overexpression of Hsp27 in MCF-7 breast cancer cells reversed DNA damage induced by adriamycin, and thereby reduced subsequent cell apoptosis. Non-phosphorylated Hsp27 accelerated ubiquitin-mediated degradation of c-Myc under normal physiological conditions. After stimulation with adriamycin, Hsp27 was phosphorylated and translocated from the cytoplasm into the nucleus, where phosphorylated Hsp27 upregulated c-Myc and Nijmegen breakage syndrome 1 (NBS1) protein levels thus leading to ATM activation. We further showed that phosphorylated Hsp27 promoted c-Myc nuclear import and stabilization by regulating T58/S62 phosphorylation of c-Myc through a protein phosphatase 2A (PP2A)-dependent mechanism. Collectively, the data presented in this study demonstrate that Hsp27, in its phosphorylation state, plays a critical role in adriamycin-resistant pathological conditions of breast cancer cells. [Display omitted] •Phosphorylated Hsp27 (p-Hsp27) contributed to ADR resistance.•p-Hsp27 facilitated ADR resistance by the c-Myc-NBS1-ATM signaling pathway.•p-Hsp27 promoted c-Myc translocation by increasing Ser62 phosphorylation of c-Myc.•p-Hsp27 maintained c-Myc stabilization by reducing Thr58 phosphorylation of c-Myc.•p-Hsp27 regulated T58/S62 phosphorylation of c-Myc through PP2A-dependent mechanism.