title: Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.
abstract: Prostate cancer (PC) is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive PC cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition, Notch3 migrated from the non-raft into the raft compartment where it colocalized with the γ-secretase complex. We also looked at human PC biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3, which, in turn, sustains proliferation of PC cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with PC.
authors.affiliation: Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Danza
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Ambrosio
authors.forename: Niccolò
authors.initials: N
authors.lastname: Sturli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lonetto
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rosati
authors.forename: Bruno Jim
authors.initials: BJ
authors.lastname: Rocca
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Ventimiglia
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: del Vecchio
authors.forename: Igor
authors.initials: I
authors.lastname: Prudovsky
authors.forename: Niccolò
authors.initials: N
authors.lastname: Marchionni
authors.forename: Francesca
authors.initials: F
authors.lastname: Tarantini
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D001706:Biopsy; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D002784:Cholesterol; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: Notch3; cholesterol; hypoxia; lipid raft; prostate cancer