Specific Roles of HSP27 S15 Phosphorylation Augmenting the Nuclear Function of HER2 to Promote Trastuzumab Resistance
- 주제(키워드) breast cancer , trastuzumab resistance , heat shock protein 27 , human epidermal growth factor receptor 2 , protein-protein interaction
- 주제(기타) Oncology
- 설명문(일반) [Hwang, Soo-Yeon; Choi, Seul-Ki; Seo, Seung Hee; Jo, Hyunji; Lee, Yun-Sil; Kwon, Youngjoo] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Shin, Jae-Ho; Na, Younghwa] CHA Univ, Coll Pharm, Pochon 487010, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 MDPI
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000172375
- 본문언어 영어
- Published As https://dx.doi.org/10.3390/cancers12061540
- PubMed https://pubmed.ncbi.nlm.nih.gov/32545363
초록/요약
Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27(S15)could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.
more