ER translocon inhibitor ipomoeassin F inhibits triple-negative breast cancer growth via blocking ER molecular chaperones.

Autor: Tao S; Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China., Yang EJ; Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China., Zong G; Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA., Mou PK; Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China., Ren G; Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China., Pu Y; Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China., Chen L; Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China., Kwon HJ; Chemical Genomics Leader Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea., Zhou J; Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas 72701, USA., Hu Z; Feinstein Institute for Medical Research, Northwell Health, 350 Community Dr., Manhasset, New York, 11030, USA., Khosravi A; Department of Chemistry, Ball State University, Muncie, Indiana 47306, USA., Zhang Q; Department of Mathematical Sciences, University of Arkansas, Arkansas 72701, USA., Du Y; Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas 72701, USA., Shi WQ; Department of Chemistry, Ball State University, Muncie, Indiana 47306, USA., Shim JS; Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.; MOE Frontiers Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
Jazyk: angličtina
Zdroj: International journal of biological sciences [Int J Biol Sci] 2023 Jul 31; Vol. 19 (13), pp. 4020-4035. Date of Electronic Publication: 2023 Jul 31 (Print Publication: 2023).
DOI: 10.7150/ijbs.82012
Abstrakt: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer where no effective therapy has been developed. Here, we report that the natural product ER translocon inhibitor ipomoeassin F is a selective inhibitor of TNBC cell growth. A proteomic analysis of TNBC cells revealed that ipomoeassin F significantly reduced the levels of ER molecular chaperones, including PDIA6 and PDIA4, and induced ER stress, unfolded protein response (UPR) and autophagy in TNBC cells. Mechanistically, ipomoeassin F, as an inhibitor of Sec61α-containing ER translocon, blocks ER translocation of PDIA6, inducing its proteasomal degradation. Silencing of PDIA6 or PDIA4 by RNA interferences or treatment with a small molecule inhibitor of the protein disulfide isomerases in TNBC cells successfully recapitulated the ipomoeassin F phenotypes, including the induction of ER stress, UPR and autophagy, suggesting that the reduction of PDIAs is the key mediator of the pharmacological effects of ipomoeassin F. Moreover, ipomoeassin F significantly suppressed TNBC growth in a mouse tumor xenograft model, with a marked reduction in PDIA6 and PDIA4 levels in the tumor samples. Our study demonstrates that Sec61α-containing ER translocon and PDIAs are potential drug targets for TNBC and suggests that ipomoeassin F could serve as a lead for developing ER translocon-targeted therapy for TNBC.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)
Databáze: MEDLINE