title: Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent 'type I' mode.
abstract: TRAIL is a promising anticancer agent, capable of inducing apoptosis in a wide range of treatment-resistant tumor cells. In 'type II' cells, the death signal triggered by TRAIL requires amplification via the mitochondrial apoptosis pathway. Consequently, deregulation of the intrinsic apoptosis-signaling pathway, for example, by loss of Bax and Bak, confers TRAIL-resistance and limits its application. Here, we show that despite resistance of Bax/Bak double-deficient cells, TRAIL-treatment resulted in caspase-8 activation and complete processing of the caspase-3 proenzymes. However, active caspase-3 was degraded by the proteasome and not detectable unless the XIAP/proteasome pathway was inhibited. Direct or indirect inhibition of XIAP by RNAi, Mithramycin A or by the SMAC mimetic LBW-242 as well as inhibition of the proteasome by Bortezomib overcomes TRAIL-resistance of Bax/Bak double-deficient tumor cells. Moreover, activation and stabilization of caspase-3 becomes independent of mitochondrial death signaling, demonstrating that inhibition of the XIAP/proteasome pathway overcomes resistance by converting 'type II' to 'type I' cells. Our results further demonstrate that the E3 ubiquitin ligase XIAP is a gatekeeper critical for the 'type II' phenotype. Pharmacological manipulation of XIAP therefore is a promising strategy to sensitize cells for TRAIL and to overcome TRAIL-resistance in case of central defects in the intrinsic apoptosis-signaling pathway.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Gillissen
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: T
authors.initials: T
authors.lastname: Overkamp
authors.forename: F
authors.initials: F
authors.lastname: Essmann
authors.forename: P G
authors.initials: PG
authors.lastname: Hemmati
authors.forename: R
authors.initials: R
authors.lastname: Preissner
authors.forename: C
authors.initials: C
authors.lastname: Belka
authors.forename: P T
authors.initials: PT
authors.lastname: Daniel
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000627:therapeutic use; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C522798:LBW242; D009842:Oligopeptides; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C066851:mithramycin A; D053148:Caspase 3; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex; D008926:Plicamycin