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RESEARCH PRODUCT
The STAT3 Inhibitor Galiellalactone Reduces IL6-Mediated AR Activity in Benign and Malignant Prostate Models
Rute B. MarquesHolger H.h. ErbZoran CuligGeorg SchaeferMartin PuhrFabian GuggenbergerJulia HoeferNicla LoritoFrédéric R. SanterFrank ClaessensWytske M. Van WeerdenFlorian HandleFlorian HandleMartina Grubersubject
Male0301 basic medicineCancer ResearchINTERLEUKIN-6LactonesProstate cancerLIGAND-INDEPENDENT ACTIVATION0302 clinical medicineProstateDEPRIVATIONANDROGEN RECEPTORGLUCOCORTICOID-RECEPTORmedicine.anatomical_structureOncologyReceptors Androgen030220 oncology & carcinogenesisAndrogensSILTUXIMAB CNTO 328GROWTHSIGNAL TRANSDUCERSignal transductionLife Sciences & BiomedicineProtein BindingSignal TransductionSTAT3 Transcription FactorENZALUTAMIDEmedicine.drug_classMice NudeModels BiologicalTMPRSS203 medical and health sciencesProtein DomainsCell Line TumorLNCaPmedicineAnimalsHumansCastrationCANCER CELLSScience & TechnologyInterleukin-6business.industryProstatic NeoplasmsDNAmedicine.diseaseAndrogenXenograft Model Antitumor AssaysAndrogen receptor030104 developmental biologyCancer researchbusinessEx vivodescription
IL6/STAT3 signaling is associated with endocrine therapy resistance in prostate cancer, but therapies targeting this pathway in prostate cancer were unsuccessful in clinical trials so far. The mechanistic explanation for this phenomenon is currently unclear; however, IL6 has pleiotropic effects on a number of signaling pathways, including the androgen receptor (AR). Therefore, we investigated IL6-mediated AR activation in prostate cancer cell lines and ex vivo primary prostate tissue cultures in order to gain a better understanding on how to inhibit this process for future clinical trials. IL6 significantly increased androgen-dependent AR activity in LNCaP cells but importantly did not influence AR activity at castrate androgen levels. To identify the underlying mechanism, we investigated several signaling pathways but only found IL6-dependent changes in STAT3 signaling. Biochemical inhibition of STAT3 with the small-molecule inhibitor galiellalactone significantly reduced AR activity in several prostate and breast cancer cell lines. We confirmed the efficacy of galiellalactone in primary tissue slice cultures from radical prostatectomy samples. Galiellalactone significantly reduced the expression of the AR target genes PSA (P < 0.001), TMPRSS2 (P < 0.001), and FKBP5 (P = 0.003) in benign tissue cultures (n = 24). However, a high heterogeneity in the response of the malignant samples was discovered, and only a subset of tissue samples (4 out of 10) had decreased PSA expression upon galiellalactone treatment. Taken together, this finding demonstrates that targeting the IL6/STAT3 pathway with galiellalactone is a viable option to decrease AR activity in prostate tissue that may be applied in a personalized medicine approach. ispartof: MOLECULAR CANCER THERAPEUTICS vol:17 issue:12 pages:2722-2731 ispartof: location:United States status: published
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-12-01 |