title: CSC-3436 switched tamoxifen-induced autophagy to apoptosis through the inhibition of AMPK/mTOR pathway.
abstract: BACKGROUND
  Triple-negative breast cancer (TNBC) lacks specific therapeutic target and limits to chemotherapy and is essential to develop novel therapeutic regimens. Increasing studies indicated that tamoxifen, a selective estrogen receptor modulators (SERMs), has anti-tumor therapeutic effect in estrogen receptor α (ERα)-negative tumor. Here, we determined whether autophagy was activated by tamoxifen in TNBC cells. Moreover, CSC-3436 displayed strong and selective growth inhibition on cancer cells. Next, we investigated the anti-proliferation effect of combination of CSC-3436 plus tamoxifen on cell death in TNBC cells.
  
  
  RESULTS
  Our study found that tamoxifen induces autophagy in TNBC cells. Endoplasmic reticulum stress and AMPK/mTOR contributed tamoxifen-induced autophagy. Interestingly, in combination treatment with CSC-3436 enhanced the anti-proliferative effect of tamoxifen. We found that CSC-3436 switched tamoxifen-induced autophagy to apoptosis via cleavage of ATG-5. Moreover, AMPK/mTOR pathway may involve in CSC-3436 switched tamoxifen-induced autophagy to apoptosis. The combination of tamoxifen and CSC-3436 produced stronger tumor growth inhibition compared with CSC-3436 or tamoxifen alone treatments in vivo.
  
  
  CONCLUSIONS
  These data indicated that CSC-3436 combined with tamoxifen may be a potential approach for treatment TNBC.
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taichung, Taiwan.
authors.forename: Sheng-Tang
authors.initials: ST
authors.lastname: Wu
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taichung, Taiwan.
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Sun
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taichung, Taiwan.
authors.forename: Tai-Lung
authors.initials: TL
authors.lastname: Cha
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taichung, Taiwan.
authors.forename: Chien-Chang
authors.initials: CC
authors.lastname: Kao
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taichung, Taiwan.
authors.forename: Sun-Yran
authors.initials: SY
authors.lastname: Chang
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan. professor.kuo@gmail.com.|Graduate institute of Pharmaceutical Chemistry, China Medical University, Taichung, 40402, Taiwan R.O.C. professor.kuo@gmail.com.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan R.O.C. tdway@mail.cmu.edu.tw.|Department of Health and Nutrition Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. tdway@mail.cmu.edu.tw.
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D013629:Tamoxifen; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK/mTOR; CSC-3436; Endoplasmic reticulum stress; Tamoxifen; Triple-negative breast cancer