title: Activation of the ER stress and calcium signaling in angiomyolipoma.
abstract: Renal angiomyolipomas (AMLs) are uncommon benign tumors that occur sporadically or as a part of tuberous sclerosis complex (TSC). Risk of life threatening hemorrhage is the main clinical concern. Although several evidences suggest that hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is crucial for these tumors, modulation of other metabolic pathways might affect tumor growth and progression. Therefore, we aimed to further characterize angiomyolipoma by TSC1/TSC2 expression, hypoxic status, expression of endoplasmic reticulum (ER) stress markers and calcium transport from the ER through the inositol 1,4,5-trisphosphate (IP3) receptors. Despite our expectations, angiomyolipoma were not hypoxic, as determined by absent expression of the carbonic anhydrase IX, which is a reliable marker of hypoxia. This was in accord with very low expression of TSC1 (that is associated with HIF activation) and a high expression of TSC2. Angiomyolipoma specimens also showed a significant upregulation of an anti-apoptotic marker Bcl2 when compared to healthy kidney tissue supporting the induction of pro-survival signaling. Moreover, angiomyolipoma specimens showed the overexpression of the ER stress markers XBP1, CHOP and ATF4 as well as of the mediators of calcium metabolism, namely the type 1 and 2, but not the type 3 IP3 receptors. These data suggest that the ER stress response, survival and calcium metabolism-related pathways but not hypoxia is an important component of the angiomyolipoma pathogenesis.
authors.forename: B
authors.initials: B
authors.lastname: Novotna
authors.forename: M
authors.initials: M
authors.lastname: Takacova
authors.forename: S
authors.initials: S
authors.lastname: Hudecova
authors.forename: L
authors.initials: L
authors.lastname: Lencesova
authors.forename: J
authors.initials: J
authors.lastname: Breza
authors.forename: A
authors.initials: A
authors.lastname: Misak
authors.forename: L
authors.initials: L
authors.lastname: Csaderova
authors.forename: S
authors.initials: S
authors.lastname: Pastorekova
authors.forename: O
authors.initials: O
authors.lastname: Krizanova
authors.forename: J
authors.initials: J
authors.lastname: Breza
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis; D018207:Angiomyolipoma / Q000473:pathology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D020013:Calcium Signaling / Q000502:physiology*; D000071231:Carbonic Anhydrase IX / Q000096:biosynthesis; D015687:Cell Hypoxia / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014402:Tuberous Sclerosis / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein / Q000096:biosynthesis; D000077005:Tuberous Sclerosis Complex 2 Protein / Q000096:biosynthesis; D000071717:X-Box Binding Protein 1 / Q000096:biosynthesis
chemical_list: C497109:ATF4 protein, human; D000951:Antigens, Neoplasm; C497249:DDIT3 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000076222:Mechanistic Target of Rapamycin Complex 1; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX
keywords: 4; 5-trisphosphate receptors.; angiomyolipoma; endoplasmic reticulum stress; inositol 1