title: The antitumor lignan Nortrachelogenin sensitizes prostate cancer cells to TRAIL-induced cell death by inhibition of the Akt pathway and growth factor signaling.
abstract: Prostate cancer cells frequently develop resistance toward androgen-deprivation and chemotherapy. To identify new approaches to treat androgen-dependent prostate cancer, we have performed a structure-activity analysis of lignan polyphenols for cancer cell specific sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that has ability to induce tumor-specific cell death. In this study, we report that the lignan nortrachelogenin (NTG) is the most efficient of the 27 tested lignan compounds in sensitizing prostate cancer cells to TRAIL-induced apoptosis. Importantly, pretreatment with NTG does not sensitize a non-malignant prostate cell line to TRAIL-induced cell death. The structural comparison of lignans reveals that the dibenzylbutyrolactone skeleton is required for the apoptosis-sensitizing activity, while substitutions at the aromatic rings do not seem to play a critical role in this lignan function. Our study also characterizes the cellular effects and molecular mechanisms involved in NTG anticancer activity. We previously reported that specific lignans inhibit the Akt survival-signaling pathway in concert with TRAIL sensitization. While NTG is also shown to be a effective inhibitor of Akt signaling, in this study we further demonstrate that NTG potently inhibits tyrosine kinase (RTK) activation in response to growth factors, such as insulin and insulin-like growth factor I (IGF-I). Our results identify NTG as a novel agent for prostate cancer therapy with ability to inhibit Akt membrane localization and activity as well as the activation of growth factor receptors (GFRs), thereby efficiently synergizing with TRAIL exposure.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Biocity, POB 123, FI-20521 Turku, Finland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Peuhu
authors.forename: Preethy
authors.initials: P
authors.lastname: Paul
authors.forename: Mika
authors.initials: M
authors.lastname: Remes
authors.forename: Thomas
authors.initials: T
authors.lastname: Holmbom
authors.forename: Patrik
authors.initials: P
authors.lastname: Eklund
authors.forename: Rainer
authors.initials: R
authors.lastname: Sjöholm
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D017705:Lignans; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C020436:nortrachelogenin; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt
keywords: Dibenzylbutyrolactone; Lignans; Nortrachelogenin; Prostate cancer; Receptor tyrosine kinase; TRAIL