Activation of the ER stress and calcium signaling in angiomyolipoma

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...

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Bibliographic Details
Published in:Neoplasma 2016, Vol.63 (5), p.687-695
Main Authors: Novotna, B, Takacova, M, Hudecova, S, Lencesova, L, Breza, Jr, J, Misak, A, Csaderova, L, Pastorekova, S, Krizanova, O, Breza, J
Format: Article
Language:English
Subjects:
Activating Transcription Factor 4 - biosynthesis
Angiomyolipoma - pathology
Antigens, Neoplasm - biosynthesis
Calcium Signaling - physiology
Carbonic Anhydrase IX - biosynthesis
Cell Hypoxia - physiology
Endoplasmic Reticulum Stress - physiology
Humans
Inositol 1,4,5-Trisphosphate Receptors - metabolism
Kidney - pathology
Kidney Neoplasms - pathology
Mechanistic Target of Rapamycin Complex 1 - metabolism
Proto-Oncogene Proteins c-bcl-2 - biosynthesis
Transcription Factor CHOP - biosynthesis
Tuberous Sclerosis - pathology
Tuberous Sclerosis Complex 1 Protein - biosynthesis
Tuberous Sclerosis Complex 2 Protein - biosynthesis
X-Box Binding Protein 1 - biosynthesis
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Summary: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.
ISSN:0028-2685
DOI:10.4149/neo_2016_505