title: Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells.
abstract: Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Josep
authors.initials: J
authors.lastname: Domingo-Domenech
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Vidal
authors.forename: Veronica
authors.initials: V
authors.lastname: Rodriguez-Bravo
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.forename: S Aidan
authors.initials: SA
authors.lastname: Quinn
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Bonal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Charytonowicz
authors.forename: Nataliya
authors.initials: N
authors.lastname: Gladoun
authors.forename: Janis
authors.initials: J
authors.lastname: de la Iglesia-Vicente
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Benson
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D018450:Disease Progression; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D053823:Hedgehog Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch; D043823:Taxoids; D000077143:Docetaxel; D051057:Proto-Oncogene Proteins c-akt