Activated stress response pathways within multicellular aggregates utilize an autocrine component

Jack, Graham D.; Cabrera, M. Carla; Manning, M. M.; Slaughter, Stephen M.; Potts, Malcolm; Helm, Richard F.

doi:10.1016/j.cellsig.2006.10.005

Cited by 10 publications

(9 citation statements)

References 47 publications

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“…In this regard, it is known that hypoxia activates IkBKb, the main upstream modulator of NF-kB, providing a possible mechanism for the activation of this transcription factor [Cummins et al, 2006]. This change could be perpetuated by a positive feedback mediated by cytokine production, since cells cultured in MTS show a cytokine auto-regulatory loop mediated by a stress response [Jack et al, 2007]. Further experiments inhibiting these loops could help to Fig.…”

Section: Discussionmentioning

confidence: 98%

NF‐kappa B is required for the development of tumor spheroids

Gallardo‐Pérez

Espinosa

Ceballos‐Cancino

et al. 2009

J of Cellular Biochemistry

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Tumor cells cultured in three-dimensional models provide a more realistic and biologically meaningful analysis of the initial phases of cancer development and drug resistance. Several studies have demonstrated that culture of cancer cells in three dimensions induces cellular resistance to a variety of anti-neoplastic drugs by poorly understood mechanisms. The role of the transcription factor NF-kappaB and inhibitors of apoptosis proteins (IAPs) in the onset and development of drug resistance during tumor spheroid growth has not been established. In this work, we found a significant increase in the activity and expression of NF-kappaB and its downstream target XIAP (X-linked IAP) in cancer cells grown as multi-cellular tumor spheroids. Blocking XIAP expression with RNA interference markedly increased the sensitivity of cancer tumor spheroid cells toward anti-neoplastic drugs, indicating a role for IAPs in establishing drug resistance. In turn, inhibition of NF-kappaB by negative dominants suppressed spheroid formation, whereas overexpression of the upstream kinase IkappaBKbeta increased their growth and resistance. The present data suggested that NF-kappaB and its downstream target XIAP were essential for the growth and drug resistance of small avascular tumor.

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Section: Discussionmentioning

confidence: 98%

NF‐kappa B is required for the development of tumor spheroids

Gallardo‐Pérez

Espinosa

Ceballos‐Cancino

et al. 2009

J of Cellular Biochemistry

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“…Therefore, the resistance to doxorubicin in cell clusters of KLE may be modulated by Akt independent pathways. Alternatively, constitutive activation may be reduced in cell monolayers and less compact spheroids [50,51] as it noted in KLE cell line.…”

Section: Discussionmentioning

confidence: 99%

The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer

2012

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BackgroundAdvanced endometrial cancer often shows resistance to clinical chemotherapy although potencies of anticancer drugs in vitro are promising. The disparity suggests that in vivo microenvironments are not recapitulated by in vitro models used for preclinical testing. However, spheroids replicate some important properties of tumours in vivo. Therefore, for the first time, we compared effects of doxorubicin and cisplatin on 3D multicellular structures and 2D cell monolayers of endometrial cancer cells.Methods3D multicellular structures were generated by culturing cancer cells on non-adherent surfaces; and for comparison cell monolayers were cultured on adherent culture plates. Ishikawa, RL95-2, and KLE cell lines were studied. Morphologies of 3D multicellular structures were examined. After 48 hours treatment with anticancer drugs, apoptosis, proliferation, glucose metabolism and vascular endothelial growth factor (VEGF) were analysed. Immunostaining of PCNA, Glut-1, p-Erk1/2, SOD-1 and p-Akt1/2/3 was also performed.ResultsDistinct 3D multicellular morphologies were formed by three different endometrial cancer cell lines. Doxorubicin induced less apoptosis in 3D multicellular structures of high grade cancer cells (RL95-2 and KLE cell lines) than in cell monolayers. Parallel alterations in Erk1/2 phosphorylation and cell proliferation might suggest they were linked and again doxorubicin had less effect on 3D multicellular structures than cell monolayers. On the other hand, there was no correlation between altered glucose metabolism and proliferation. The responses depended on cancer cell lines and were apparently not mediated by altered Glut-1 levels. The level of SOD-1 was high in 3D cell cultures. The effects on VEGF secretion were various and cancer cell line dependent. Importantly, both doxorubicin and cisplatin had selective paradoxical stimulatory effects on VEGF secretion. The microenvironment within 3D multicellular structures sustained Akt phosphorylation, consistent with it having a role in anchorage-independent pathways.ConclusionsThe cancer cells responded to microenvironments in a distinctive manner. 3D multicellular structures exhibited greater resistance to the agents than 2D monolayers, and the differences between the culture formats were dependent on cancer cell lines. The effects of anticancer drugs on the intracellular mediators were not similar in 3D and 2D cultures. Therefore, using 3D cell models may have a significant impact on conclusions derived from screening drugs for endometrial carcinomas.

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“…Pre-treatment of the endothelial cell layer with an inhibitor of the TGF-β receptor lead to significant blockage of ATF3 nuclear localization. Previous reports have linked ATF3 up-regulation to a preceding or concurrent induction and phosphorylation of the transcription factor c-Jun and have shown that the increase in ATF3 expression can be blocked by knockdown of c-Jun [ 80 – 82 ]. While previous reports have demonstrated that ATF3 homodimeric complexes act as repressors for gene transcription, heterodimeric ATF3/c-Jun complexes seem to act as activators for gene transcription [ 78 , 83 ].…”

Section: Discussionmentioning

confidence: 99%

TGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-β Receptor Pathway in Human Aortic Endothelial Cells

et al. 2015

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Studies have suggested a link between the transforming growth factor beta 1 (TGF-β1) signaling cascade and the stress-inducible activating transcription factor 3 (ATF3). We have demonstrated that triglyceride-rich lipoproteins (TGRL) lipolysis products activate MAP kinase stress associated JNK/c-Jun pathways resulting in up-regulation of ATF3, pro-inflammatory genes and induction of apoptosis in human aortic endothelial cells. Here we demonstrate increased release of active TGF-β at 15 min, phosphorylation of Smad2 and translocation of co-Smad4 from cytosol to nucleus after a 1.5 h treatment with lipolysis products. Activation and translocation of Smad2 and 4 was blocked by addition of SB431542 (10 μM), a specific inhibitor of TGF-β-activin receptor ALKs 4, 5, 7. Both ALK receptor inhibition and anti TGF-β1 antibody prevented lipolysis product induced up-regulation of ATF3 mRNA and protein. ALK inhibition prevented lipolysis product-induced nuclear accumulation of ATF3. ALKs 4, 5, 7 inhibition also prevented phosphorylation of c-Jun and TGRL lipolysis product-induced p53 and caspase-3 protein expression. These findings demonstrate that TGRL lipolysis products cause release of active TGF-β and lipolysis product-induced apoptosis is dependent on TGF-β signaling. Furthermore, signaling through the stress associated JNK/c-Jun pathway is dependent on TGF-β signaling suggesting that TGF-β signaling is necessary for nuclear accumulation of the ATF3/cJun transcription complex and induction of pro-inflammatory responses.

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Activated stress response pathways within multicellular aggregates utilize an autocrine component

Cited by 10 publications

References 47 publications

NF‐kappa B is required for the development of tumor spheroids

NF‐kappa B is required for the development of tumor spheroids

The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer

TGRL Lipolysis Products Induce Stress Protein ATF3 via the TGF-β Receptor Pathway in Human Aortic Endothelial Cells

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