Keratin 8 and 18 Loss in Epithelial Cancer Cells Increases Collective Cell Migration and Cisplatin Sensitivity through Claudin1 Up-regulation

Fortier, Anne-Marie; Asselin, Éric; Cadrin, Monique

doi:10.1074/jbc.m112.428920

Cited by 190 publications

(163 citation statements)

References 79 publications

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“…K8/18 are found mainly in simple-type epithelia and protect cells from injury and apoptosis (23,31,44). K8 or K8/18 loss increases the membrane targets of Fas and the sensitivity to FasL and cisplatin (24,37,38). Although Piwil2 and keratin 8 both provide resistance to apoptosis, by now there is no definite evidence on their relationship.…”

Section: Discussionmentioning

confidence: 99%

“…To identify novel Piwil2-interacting proteins and their potential functions in tumor cells, we performed a bacterial twohybrid screen of a human HeLa cDNA expression library with Piwil2 as the bait. By the sequencing of positive clones, we identified one Piwil2-interacting peptide as C terminal (amino acids [aa] 309 to 483) to K8 which is well known to protect the cell from Fas-mediated apoptosis and injury (23,24,31,37).…”

Section: Piwil2 Knockdown Increases Cell Sensitivity To Fas-mediated mentioning

confidence: 99%

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Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Jiang

Zhao

et al. 2014

Molecular and Cellular Biology

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bThe piwi-like 2 (piwil2) gene is widely expressed in tumors and protects cells from apoptosis induced by a variety of stress stimuli. However, the role of Piwil2 in Fas-mediated apoptosis remains unknown. Here, we present evidence that Piwil2 inhibits Fasmediated apoptosis. By a bacterial two-hybrid screening, we identify a new Piwil2-interacting partner, keratin 8 (K8), a major intermediate filament protein protecting the cell from Fas-mediated apoptosis. Our results show that Piwil2 binds to K8 and p38 through its PIWI domain and forms a Piwil2/K8/P38 triple protein-protein complex. Thus, Piwil2 increases the phosphorylation level of K8 Ser-73 and then inhibits ubiquitin-mediated degradation of K8. As a result, the knockdown of Piwil2 increases the Fas protein level at the membrane. In addition to our previous finding that Piwil2 inhibits the expression of p53 through the Src/ STAT3 pathway, here we demonstrate that Piwil2 represses p53 phosphorylation through p38. Our present study indicates that Piwil2 plays a role in Fas-mediated apoptosis for the first time and also can affect p53 phosphorylation in tumor cells, revealing a novel mechanism of Piwil2 in apoptosis, and supports that Piwil2 plays an active role in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Piwil2 Knockdown Increases Cell Sensitivity To Fas-mediated mentioning

confidence: 99%

Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Jiang

Zhao

et al. 2014

Molecular and Cellular Biology

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“…Oncogenes, which activate Ras signaling, stimulate expression of K18 through transcription factors [76]. However, aberrant K8 and K18 expression has been noticed in particularly invasive carcinomas [77,78]. K18 was found to be a substrate of the cysteine-aspartic proteases during epithelial apoptosis [77].…”

Section: Anti-keratin Agentsmentioning

confidence: 99%

Targeting the Cytoskeleton with Plant-Bioactive Compounds in Cancer Therapy

Ardelean¹

2017

Cytoskeleton - Structure, Dynamics, Function and Disease

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In this overview we describe the main plant-derived bioactive compounds used in cancer therapy which has the cell cytoskeleton as therapeutic target. Three major classes of these compounds are described: antimitotics with microtubule-destabilizing and-stabilizing efects, plant-bioactive compounds that interact with intermediate ilaments/actin, and plant-bioactive compounds that interact with intermediate ilaments like keratins and vimentin. We also focus on the molecular aspects of interactions with their cellular targets: microtubules, intermediate ilaments, and microilaments. Some critical aspects of cardiac side efects of cancer chemotherapy are also discussed, focusing on cardiac cytoskeleton and protective efect of plant-derived compounds. The application of plant bioactives in the treatment of cancer has resulted in increased therapeutic eicacy through targeting the cytoskeleton, respectively, prevention of the injury of cytoskeletal components elicited by chemotherapeutics.

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“…Reduced expression of CK8 and CK18 in these cells led to hyperactivity of PI3K, NF-kB and Akt, as well as increased expression of MMP2 and MMP9. Although it is recognised that CK8 and CK18 are involved in intracellular signalling and that 43 Therefore, it is likely that, in addition to loss of K8 and K18 being a hallmark of EMT, modulation of these proteins at the transcriptional level influences cancer cell phenotype by orchestrating structural alterations that enable cells to escape from the primary tumour.…”

Section: Cytokeratins 8 18 and 19mentioning

confidence: 99%

Molecular alterations that drive breast cancer metastasis to bone

2015

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Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis.

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Keratin 8 and 18 Loss in Epithelial Cancer Cells Increases Collective Cell Migration and Cisplatin Sensitivity through Claudin1 Up-regulation

Cited by 190 publications

References 79 publications

Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Piwil2 Inhibits Keratin 8 Degradation through Promoting p38-Induced Phosphorylation To Resist Fas-Mediated Apoptosis

Targeting the Cytoskeleton with Plant-Bioactive Compounds in Cancer Therapy

Molecular alterations that drive breast cancer metastasis to bone

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