Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors

Experiments in space either on orbital missions on-board the ISS, or in suborbital missions using sounding rockets, like TEXUS as well as parabolic flight campaigns are still the gold standard to achieve real microgravity conditions in the field of gravitational biology and medicine. However, during launch, and in flight, hypergravity and vibrations occur which might interfere with the effects of microgravity. It is therefore important to know these effects and discriminate them from the microgravity effects. This can be achieved by ground-based facilities like centrifuges or vibration platforms. Recently, we have conducted several experiments with different thyroid cancer cell lines. This study, as part of the ESA-CORA-GBF 2010-203 project, focused on the influence of vibration and hypergravity on benign human thyroid follicular epithelial cells (Nthy-ori 3-1 cell line). Gene and in part protein expression regulation under both conditions were analyzed for VCAN, ITGA10, ITGB1, OPN, ADAM19, ANXA1, TNFA, ABL2, ACTB, PFN2, TLN1, EZR, RDX, MSN, CTGF, PRKCA, and PRKAA1 using quantitative real-time PCR and Western Blot. We found that hypergravity and vibration affected genes and proteins involved in the extracellular matrix, the cytoskeleton, apoptosis, cell growth and signaling. Vibration always led to a down-regulation, whereas hypergravity resulted in a more heterogeneous expression pattern. Overall we conclude that both conditions can influence gene regulation and production of various genes and proteins. As a consequence, it is important to perform control experiments on hypergravity and vibration facilities in parallel to flight experiments

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“…This is consistent with the results of the OPN gene expression since osteopontin exerts an anti-apoptotic effect (Hsu et al 2014). …”

Section: Impact Of Hypergravity On Genes Involved In Apoptosissupporting

confidence: 85%

The Impact of Hypergravity and Vibration on Gene and Protein Expression of Thyroid Cells

Wehland

Warnke

Frett³

et al. 2016

Microgravity Sci. Technol.

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“…The anti-apoptotic effects of OPN have been found in some tumors (Geissinger et al, 2002;Hsu et al, 2014). OPN has been shown to induce angiogenesis of endothelial cells through the activation of PI3K/Akt pathway in tumors (Dai et al, 2009).…”

Section: Discussionmentioning

confidence: 95%

Recombinant osteopontin attenuates experimental cerebral vasospasm following subarachnoid hemorrhage in rats through an anti-apoptotic mechanism

Liu

et al. 2015

Brain Research

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“…There are several reports that link PKCd with the regulation of the Wnt/b-catenin pathway (16), and other reports link this signaling pathway with Mcl-1 modulation (17)(18)(19). On the basis of these articles, we propose that PKCd would modulate Mcl-1 by regulation of the Wnt/b-catenin pathway in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…PKCd negatively modulates the canonical Wnt/b-catenin pathway (16) and this pathway modulates Mcl-1 expression in several tumor types (17)(18)(19). As we observed a prominent increase of Mcl-1 L in PKCd-silenced cells and this protein has an important role in paclitaxel-induced apoptosis, we examined whether PKCd modulates Mcl-1 expression through the Wnt/b-catenin pathway in prostate cancer cells.…”

Section: Pkcd Regulates Mcl-1 Degradation By Negative Modulation Of Wmentioning

confidence: 98%

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

Flores

Castilla

Gasca

et al. 2016

Molecular Cancer Therapeutics

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Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCd silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCd seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/b-catenin pathway. PKCd silencing induces activation of Wnt/b-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3b inactivation and consequently in the stabilization of b-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/b-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCd. Finally, we observe that high Gleason score prostate tumors lose PKCd expression and this correlates with higher activation of b-catenin, inactivation of GSK3b, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/b-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCd expression.

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Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors

Cited by 11 publications

References 48 publications

The Impact of Hypergravity and Vibration on Gene and Protein Expression of Thyroid Cells

The Impact of Hypergravity and Vibration on Gene and Protein Expression of Thyroid Cells

Recombinant osteopontin attenuates experimental cerebral vasospasm following subarachnoid hemorrhage in rats through an anti-apoptotic mechanism

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

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