Survivin Expression in Tuberous Sclerosis Complex Cells

Carelli, Stephana; Lesma, Elena; Paratore, Simona; Grande, V.; Zadra, Giorgia; Bòsari, Silvano; Giulio, Anna Maria Di; Gorio, Alfredo

doi:10.2119/2006-00091.carelli

Cited by 21 publications

(12 citation statements)

References 57 publications

(66 reference statements)

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“…Thus, our results suggest that the process of apoptosis is inhibited in angiomyolipoma samples. Inhibited apoptosis in angiomyolipoma was observed also by Carelli and co-workers [23], who clearly showed that angiomyolipoma-derived human smooth muscle TSC2-/-cells express the apoptosis inhibitor protein survivin when exposed to IGF-1. Survivin originally was isolated as a member of IAP family, and it was suggested that it plays a fundamental role in inhibiting apoptosis and regulating the mitotic process and cell proliferation [24].…”

Section: Discussionsupporting

confidence: 56%

Activation of the ER stress and calcium signaling in angiomyolipoma

NOVOTNA¹,

Takáčová²,

Hudecová³

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 56%

Activation of the ER stress and calcium signaling in angiomyolipoma

NOVOTNA¹,

Takáčová²,

Hudecová³

et al. 2016

neo

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“…The rate of proliferation of TSC2 − / − ASM cells is sensitive to the addition of EGF to the growth medium, while secretion of IGF-I is involved in survival [15], [16]. Here, we report that the viral-induced expression of tuberin in TSC2 −/− ASM cells greatly reduced the growth rate, EGF ceased to be a required growth factor, and instead, it inhibited proliferation.…”

Section: Discussionmentioning

confidence: 68%

Anti-EGFR Antibody Efficiently and Specifically Inhibits Human TSC2−/− Smooth Muscle Cell Proliferation. Possible Treatment Options for TSC and LAM

et al. 2008

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Background Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC2−/− ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2−/− ASM cell proliferation is EGF-dependent.Methods and FindingsEffects of EGF on proliferation of TSC2−/− ASM cells and TSC2−/− ASM cells transfected with TSC2 gene were determined. In contrast to TSC2−/− ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC2−/− ASM cells. Exposure of TSC2−/− ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC2−/− cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2−/− ASM cells to rapamycin reduced the proliferation rate, but only when added at plating time. Although rapamycin efficiently inhibited S6 phosphorylation, it was less efficient than anti-EGFR antibody in reverting HMB45 reactivity and blocking ERK phosphorylation. In TSC2−/− ASM cells specific PI3K inhibitors (e.g. LY294002, wortmannin) and Akt1 siRNA had little effect on S6 and ERK phosphorylation. Following TSC2-gene transfection, Akt inhibitor sensitivity was observed.ConclusionOur results show that an EGF independent pathway is more important than that involving IGF-I for growth and survival of TSC−/− ASM cells, and such EGF-dependency is the result of the lack of tuberin.

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“…Survivin is a member of the inhibitors of apoptosis (IAP) gene family which is recently described and plays an important role in the inhibition of apoptosis and control of cell division (Ambrosini et al., 1997; Troeger et al., 2007; Stauber et al., 2007; Carelli et al., 2007). It deserves attention as a selective target for cancer therapy because it is highly expressed in most malignancies and embryonic tissues but is undetectable or expressed at a very low level in normal adult tissues (Tanabe et al., 2004; Yamashita et al., 2007; Gazzaniga et al., 2003; Cohen et al., 2003; Gordon et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

Effects of Survivin on cell proliferation and apoptosis in MG‐63 cells in vitro

Liang¹,

Da²,

Zhang³

et al. 2009

Cell Biology International

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Osteosarcoma is the most frequent primary malignant tumor of the skeleton and occurs mainly in children and adolescent. The prognosis of osteosarcoma is very poor due to its aggressive and no effective treatment. This study is the first to investigate the anti-cancer effects of antisense pEGFP-C1-Survivin on human osteosarcoma cells. It was shown in our results that Survivin blockaded could significantly induce apoptosis and inhibit the invasive of osteosarcoma cells line MG-63. The effects were probably produced by the decreased expression of Survivin induced by antisense pEGFP-C1-Survivin which was examined by RT-PCR and western blotting. All these suggested that Survivin should be very important in the development of osteosarcoma and Survivin blockaded by using antisense pEGFP-C1-Survivin could markedly inhibit the proliferation and invasion of osteosarcoma cells line MG-63, partially reversed their malignant phenotype. Targeting Survivin might be a promising option in the treatment of osteosarcoma.

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Survivin Expression in Tuberous Sclerosis Complex Cells

Cited by 21 publications

References 57 publications

Activation of the ER stress and calcium signaling in angiomyolipoma

Activation of the ER stress and calcium signaling in angiomyolipoma

Anti-EGFR Antibody Efficiently and Specifically Inhibits Human TSC2−/− Smooth Muscle Cell Proliferation. Possible Treatment Options for TSC and LAM

Effects of Survivin on cell proliferation and apoptosis in MG‐63 cells in vitro

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