A Novel Kinase Inhibitor of FADD Phosphorylation Chemosensitizes through the Inhibition of NF-κB

Schinske, Katrina; Nyati, Shyam; Khan, Amjad P.; Williams, Terence M.; Johnson, Timothy D.; Ross, Brian D.; Pérez-Tomás, Ricardo; Rehemtulla, Alnawaz

doi:10.1158/1535-7163.mct-11-0362

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…3B). To evaluate a requirement for CK1α, the kinase that phosphorylates FADD (14, 27–28), we treated K Luc cells with a CK1α inhibitor, CKI-7., We observed a marked decrease in the proliferative ability of CKI-7-treated K Luc cells, whereas that of CKI-7-treated KF Luc or Luc cells was not substantially affected (Fig. 3C).…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of FADD by the kinase CK1α promotes KRAS ^G12D -induced lung cancer

et al. 2015

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Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Activating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. We found that the abundance of phosphorylated FADD correlated with that of mutant KRAS in patient lung cancer tissues. Using immunohistochemistry analysis and in vivo imaging of conditional mouse models of KRASG12D-driven lung cancer, we found that the deletion of the gene encoding FADD suppressed tumor growth, reduced the proliferative index of cells, and decreased the activation of downstream effectors of the RAS–MAPK (mitogen-activated protein kinase) pathway that promote the cell cycle, including retinoblastoma (RB) and cyclin D1. In mouse embryonic fibroblasts, the induction of mitosis upon activation of KRAS required FADD and the phosphorylation of FADD by CK1α (casein kinase 1α). Deleting the gene encoding CK1α in KRAS-mutant mice abrogated the phosphorylation of FADD and suppressed lung cancer development. Phosphorylated FADD was most abundant during the G2/M phase of the cell cycle, and mass spectrometry revealed that phosphorylated FADD interacted with kinases that mediate the G2/M transition, including PLK1 (Polo-like kinase 1), AURKA (Aurora kinase A) and BUB1 (budding uninhibited by benzimidazoles 1). This interaction was decreased in cells treated with a CKI-7, a CK1α inhibitor. Therefore, as the kinase that phosphorylates FADD downstream of RAS, CK1α may be a therapeutic target for KRAS-driven lung cancer.

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Section: Resultsmentioning

confidence: 99%

Phosphorylation of FADD by the kinase CK1α promotes KRAS ^G12D -induced lung cancer

et al. 2015

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“…FADD is a cytosolic adapter protein essential for mediating death receptor‐induced apoptosis . FADD is one of the most important apoptotic genes in cells and its downregulation has been observed in many cancers and it is classified as a cancer driver gene .…”

Section: Discussionmentioning

confidence: 99%

Simultaneous downregulation of miR‐21 and miR‐155 through oleuropein for breast cancer prevention and therapy

Abtin

Alivand

Khaniani

et al. 2018

J of Cellular Biochemistry

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Breast cancer (BC) is the leading cause of cancer mortality in women worldwide. It recently was proven that miRNAs play a critical role in BC development. The use of natural agents for control of cancer by modulating miRNAs is promising. Oleuropein is a natural polyphenolic agent with anti-neoplastic properties and is well tolerated by humans. This study was undertaken to determine the therapeutic effects of oleuropein through modulation of master oncomiRs (miR-21 and miR-155) in BC cells. The present study provides the first link between miRNA and oleuropein as a mechanism in BC. MCF-7 cells were tested with and without oleuropein and the cell viability, apoptosis, and migration were examined. The effect of oleuropein on miR-21 and miR-155 expression was assessed through qRT-PCR. It was found that oleuropein induced apoptosis and retarded cell migration and invasion in a dose-dependent manner in the human MCF7 BC cell line. It was observed that oleuropein significantly decreased expression of both miR-21 and miR-155 over time in a dose-dependent manner. These results demonstrate that oleuropein is a potential therapeutic and preventive agent for BC. Oleuropein exhibits an anti-cancer effect by modulation of tumor suppressor gene expression, which is targeted by oncomiRs.

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“…It is possible that re-localization of FADD to the nucleus following its phosphorylation19,42 may play a major role in the dysregulation of apoptosis in human lymphomas as reported for murine T-ALL 43. pFADD overexpression has also been linked to increased activity of the anti-apoptotic NF-κB protein 22,44. and activation of the c-jun NH2-terminal kinase (JNK) signaling pathway,24,30 both of which are implicated in T-cell lymphomagenesis 45,46.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Phosphorylated FADD in Anaplastic Large Cell and Other T-Cell Lymphomas

et al. 2014

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FAS-associated protein with death domain (FADD) is a major adaptor protein involved in extrinsic apoptosis, embryogenesis, and lymphocyte homeostasis. Although abnormalities of the FADD/death receptor apoptotic pathways have been established in tumorigenesis, fewer studies have analyzed the expression and role of phosphorylated FADD (pFADD). Our identification of FADD as a lymphoma-associated autoantigen in T-cell lymphoma patients raises the possibility that pFADD, with its correlation with cell cycle, may possess role(s) in human T-cell lymphoma development. This immunohistochemical study investigated pFADD protein expression in a range of normal tissues and lymphomas, particularly T-cell lymphomas that require improved therapies. Whereas pFADD was expressed only in scattered normal T cells, it was detected at high levels in T-cell lymphomas (eg, 84% anaplastic large cell lymphoma and 65% peripheral T cell lymphomas, not otherwise specified). The increased expression of pFADD supports further study of its clinical relevance and role in lymphomagenesis, highlighting phosphorylation of FADD as a potential therapeutic target.

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A Novel Kinase Inhibitor of FADD Phosphorylation Chemosensitizes through the Inhibition of NF-κB

Cited by 14 publications

References 36 publications

Phosphorylation of FADD by the kinase CK1α promotes KRAS ^G12D -induced lung cancer

Phosphorylation of FADD by the kinase CK1α promotes KRAS ^G12D -induced lung cancer

Simultaneous downregulation of miR‐21 and miR‐155 through oleuropein for breast cancer prevention and therapy

Increased Expression of Phosphorylated FADD in Anaplastic Large Cell and Other T-Cell Lymphomas

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A Novel Kinase Inhibitor of FADD Phosphorylation Chemosensitizes through the Inhibition of NF-κB

Cited by 14 publications

References 36 publications

Phosphorylation of FADD by the kinase CK1α promotes KRAS G12D -induced lung cancer

Phosphorylation of FADD by the kinase CK1α promotes KRAS G12D -induced lung cancer

Simultaneous downregulation of miR‐21 and miR‐155 through oleuropein for breast cancer prevention and therapy

Increased Expression of Phosphorylated FADD in Anaplastic Large Cell and Other T-Cell Lymphomas

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Phosphorylation of FADD by the kinase CK1α promotes KRAS ^G12D -induced lung cancer

Phosphorylation of FADD by the kinase CK1α promotes KRAS ^G12D -induced lung cancer