Carcinoma Matrix Controls Resistance to Cisplatin through Talin Regulation of NF-kB

Eberle, Karen E.; Sansing, Hope A.; Szaniszlo, Peter; Resto, Vicente A.; Berrier, Allison L.

doi:10.1371/journal.pone.0021496

Cited by 37 publications

(26 citation statements)

References 59 publications

(96 reference statements)

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“…Earlier studies have shown that constitutive NF-kB activity reduces sensitivity to cisplatin (22)(23)(24)(25)(26). To determine whether the NF-kB inhibitory component of MLN4924 0 s pharmacodynamic effects was a major factor contributing to its ability to sensitize ovarian cancer cells to cisplatin, we used shRNA to target the expression of the p65 NF-kB subunit.…”

Section: Mln4924 Augments the Cytostatic And Proapoptotic Effects Of mentioning

confidence: 99%

Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer

Nawrocki

Kelly

Smith

et al. 2013

Clinical Cancer Research

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Purpose: Ovarian cancer has the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure and novel therapeutic strategies are urgently needed. MLN4924 is a NEDDylation inhibitor currently under investigation in multiple phase I studies. We investigated its anticancer activity in cisplatin-sensitive and -resistant ovarian cancer models.Experimental Design: Cellular sensitivity to MLN4924/cisplatin was determined by measuring viability, clonogenic survival, and apoptosis. The effects of drug treatment on global protein expression, DNA damage, and reactive oxygen species generation were determined. RNA interference established natural born killer/bcl-2-interacting killer (NBK/BIK) as a regulator of therapeutic sensitivity. The in vivo effects of MLN4924/cisplatin on tumor burden and key pharmacodynamics were assessed in cisplatin-sensitive and -resistant xenograft models.Results: MLN4924 possessed significant activity against both cisplatin-sensitive and -resistant ovarian cancer cells and provoked the stabilization of key NEDD8 substrates and regulators of cellular redox status. Notably, MLN4924 significantly augmented the activity of cisplatin against cisplatin-resistant cells, suggesting that aberrant NEDDylation may contribute to drug resistance. MLN4924 and cisplatin cooperated to induce DNA damage, oxidative stress, and increased expression of the BH3-only protein NBK/BIK. Targeted NBK/BIK knockdown diminished the proapoptotic effects of the MLN4924/cisplatin combination. Administration of MLN4924 to mice bearing ovarian tumor xenografts significantly increased the efficacy of cisplatin against both cisplatin-sensitive and -resistant tumors.Conclusions: Our collective data provide a rationale for the clinical investigation of NEDD8-activating enzyme (NAE) inhibition as a novel strategy to augment cisplatin efficacy in patients with ovarian cancer and other malignancies.

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Section: Mln4924 Augments the Cytostatic And Proapoptotic Effects Of mentioning

confidence: 99%

Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer

Nawrocki

Kelly

Smith

et al. 2013

Clinical Cancer Research

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“…6d, P<0.05). Transcription of Snail, ZEb1, SLUG, and SIP1 is dependent upon NF-κB, so one of its inhibitors, Bay11-7082, was applied to examine the potential role of NF-κB [25]. Compared with vehicle, pretreatment with this NF-κB inhibitor modestly antagonized talinsiRNA-triggered reduction of three factors: Snail, ZEb1, and SLUG (Fig.…”

Section: Talin Regulates E-cadherin At the Transcriptional Level In Tmentioning

confidence: 99%

“…For example, in some cells, talin/vinculin is highly expressed, whereas E-cadherin expression is significantly inhibited in others [24]. Studies have shown that talin can induce expression of nuclear factor-kappa B (NF-κB) and that the NF-κB pathway is closely associated with the transcriptional factors of E-cadherin, such as snail, zinc finger E-box binding homeobox 1 (ZEB1), SLUG, and Smad-interacting protein1 (SIP1), which can repress E-cadherin transcription [25].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Intracellular Structural Tension by Talin in the Axon Growth and Regeneration

et al. 2015

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Intracellular tension is the most important characteristic of neuron polarization as well as the growth and regeneration of axons, which can be generated by motor proteins and conducted along the cytoskeleton. To better understand this process, we created Förster resonance energy transfer (FRET)-based tension probes that can be incorporated into microfilaments to provide a real-time measurement of forces in neuron cytoskeletons. We found that our probe could be used to assess the structural tension of neuron polarity. Nerve growth factor (NGF) upregulated structural forces, whereas the glial-scar inhibitors chondroitin sulfate proteoglycan (CSPG) and aggrecan weakened such forces. Notably, the tension across axons was distributed uniformly and remarkably stronger than that in the cell body in NGF-stimulated neurons. The mechanosensors talin/vinculin could antagonize the effect of glial-scar inhibitors via structural forces. However, E-cadherin was closely associated with glial-scar inhibitor-induced downregulation of structural forces. Talin/vinculin was involved in the negative regulation of E-cadherin transcription through the nuclear factor-kappa B pathway. Collectively, this study clarified the mechanism underlying intracellular tension in the growth and regeneration of axons which, conversely, can be regulated by talin and E-cadherin.

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“…We analyzed a 7.9-kb region of sequence (−2215 to + 5686 bp of TSS), which was chosen because it is roughly equally distributed around a cluster of histone acetylation marks in the vicinity of the TSS (Rosenbloom et al 2013). This sequence was used to query the sequences corresponding to the response element (RE) of several transcription factors participating in neuron survival, apoptosis, or related processes (Table 1) (Hofer-Warbinek et al 2004;Miloso et al 2004;Marrero and Bencherif 2009;Cheung et al 2009;Chung et al 2011;Eberle et al 2011), to calculate the expected and observed frequencies of each RE. Of the six transcription factor RE analyzed, those recognized by NF-κB were statistically higher in number of occurrences than expected (Fig.…”

Section: Bag2 Expression Is Negatively Regulated By Nf-κb In Undiffermentioning

confidence: 99%

BAG2 Is Repressed by NF-κB Signaling, and Its Overexpression Is Sufficient to Shift Aβ1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma

2015

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Amyloid-beta (Aβ) binds to various neuronal receptors and elicits a context- and dose-dependent toxic or trophic response from neurons. The molecular mechanisms for this phenomenon are presently unknown. The cochaperone BAG2 has been shown to mediate important cellular responses to stress, including cell cycle arrest and apoptosis. Here, we use SH-SY5Y neuroblastoma cells to characterize BAG2 expression and regulation and investigate the involvement of BAG2 in Aβ1-42-mediated neurotrophism or neurotoxicity in the context of differentiation. We report that BAG2 is upregulated on differentiation of SH-SY5Y cells into neuron-like cells. This increase in BAG2 expression is accompanied by a change in response to treatment with Aβ1-42 from neurotrophic to neurotoxic. Further, overexpression of BAG2 in undifferentiated SH-SY5Y cells was sufficient to induce the change from neurotrophic to neurotoxic response. Of several transcription factors queried, the putative BAG2 promoter had a higher-than-expected occurrence of response elements (RE) for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with JSH-23, a potent inhibitor of NF-κB, caused a marked increase in BAG2 mRNA expression, suggesting that NF-κB is a repressor of BAG2 transcription in undifferentiated SH-SY5Y cells. Together, these data suggest that NF-κB-mediated modulation of BAG2 expression constitutes a "switch" that regulates the shift between the neurotrophic and neurotoxic effects of Aβ1-42.

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Carcinoma Matrix Controls Resistance to Cisplatin through Talin Regulation of NF-kB

Cited by 37 publications

References 59 publications

Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer

Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer

Regulation of Intracellular Structural Tension by Talin in the Axon Growth and Regeneration

BAG2 Is Repressed by NF-κB Signaling, and Its Overexpression Is Sufficient to Shift Aβ1-42 from Neurotrophic to Neurotoxic in Undifferentiated SH-SY5Y Neuroblastoma

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