Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling

Chen, Jian; Shen, Qiong; Labow, Mark; Gaither, L. Alex

doi:10.1158/0008-5472.can-10-3761

Cited by 23 publications

(26 citation statements)

References 42 publications

(64 reference statements)

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“…45-3192); PKD2-2, 59-AAUGACCUUAACUGCCACGUCCCGG-39 (Azoitei et al, 2010); PKD3-1, 59-GAACGAGUCUUUGUAGUAAtt-39 (Silencer Selected Validated siRNA, catalog no. 4390824); PKD3-2, 59-GAAAGUUCCAC-ACACAUUU-39 (Chen et al, 2011); HDAC1, 59-CAGCGACUGUUUGAGAA-CCTT-39 and 59-CUAAUGAGCUUCCAUACAATT-39 (Senese et al, 2007).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

Zou

Zeng

et al. 2012

Journal of Cell Science

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SummaryAlthough protein kinase D3 (PKD3) has been shown to contribute to prostate cancer cell growth and survival, the role of PKD in prostate cancer cell motility remains unclear. Here, we show that PKD2 and PKD3 promote nuclear factor kappa B (NF-kB) signaling and urokinase-type plasminogen activator (uPA) expression/activation, which are crucial for prostate cancer cell invasion. Silencing of endogenous PKD2 and/or PKD3 markedly decreased prostate cancer cell migration and invasion, reduced uPA and uPA receptor (uPAR) expression and increased plasminogen activator inhibitor-2 (PAI-2) expression. These results were further substantiated by the finding that PKD2 and PKD3 promoted the activity of uPA and matrix metalloproteinase 9 (MMP9). Furthermore, depletion of PKD2 and/or PKD3 decreased the level of binding of the p65 subunit of NF-kB to the promoter of the gene encoding uPA (PLAU), suppressing transcriptional activation of uPA. Endogenous PKD2 and PKD3 interacted with inhibitor of NF-kB (IkB) kinase b (IKKb); PKD2 mainly regulated the phosphorylated IKK (pIKK)-phosphorylated IkB (pIkB)-IkB degradation cascade, p65 nuclear translocation, and phosphorylation of Ser276 on p65, whereas PKD3 was responsible for the phosphorylation of Ser536 on p65. Conversely, inhibition of uPA transactivation by PKD3 silencing was rescued by constitutive Ser536 p65 phosphorylation, and reduced tumor cell invasion resulting from PKD2 or PKD3 silencing was rescued by ectopic expression of p65. Interestingly, PKD3 interacted with histone deacetylase 1 (HDAC1), suppressing HDAC1 expression and decreasing its binding to the uPA promoter. Moreover, depletion of HDAC1 resulted in recovery of uPA transactivation in PKD3-knockdown cells. Taken together, these data suggest that PKD2 and PKD3 coordinate to promote prostate cancer cell invasion through p65 NF-kB-and HDAC1-mediated expression and activation of uPA.

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Section: Chemicals and Reagentsmentioning

confidence: 99%

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

Zou

Zeng

et al. 2012

Journal of Cell Science

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“…In this instance, the siRNA knockdown of PRKD3 reduced the IC 50 of both RAF265 and vemurafenib in multiple melanoma cell lines and prevented the reactivation of MAPK signaling following drug treatment 89 . In BRAF V600E mutant cell lines lacking PTEN expression, PRKD3 activity further contributed to resistance through the reactivation of PI3K/AKT signaling following RAF inhibition 89 .…”

Section: Introductionmentioning

confidence: 86%

“…Other recent studies identified protein kinase D3 (PRKD3) as being a potential mediator of intrinsic resistance to the RAF inhibitors RAF265 and vemurafenib 89 (Figure 3). In this instance, the siRNA knockdown of PRKD3 reduced the IC 50 of both RAF265 and vemurafenib in multiple melanoma cell lines and prevented the reactivation of MAPK signaling following drug treatment 89 .…”

Section: Introductionmentioning

confidence: 99%

Targeting Mutant BRAF in Melanoma

Kudchadkar¹,

Paraiso²,

Smalley³

2012

The Cancer Journal

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The discovery of activating BRAF mutations in ~50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. In this commentary we review the latest research delineating the role of mutant BRAF in melanoma initiation and progression and discuss the remarkable 10-year journey leading up to the recent FDA-approval of the small molecule BRAF inhibitor vemurafenib. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. It is hoped that our evolving understanding of melanoma genetics and intracellular signaling coupled with a growing armamentarium of signal transduction inhibitors will lead to significant improvements in the level and durability of therapeutic response in metastatic melanoma.

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“…(86, 87) In preclinical studies, these agents had broad activity against both BRAF mutant and wild-type cell lines. (86–91) Though there was some initial enthusiasm of sorafenib in combination with chemotherapy, it has been proven to be ineffective as a single-agent and in combination with chemotherapy in numerous phase I, II, and III trials. (92–98) Additionally, RAF265 has been shown to be similarly ineffective.…”

Section: Molecular Signaling In Melanomamentioning

confidence: 99%

Understanding the Biology of Melanoma and Therapeutic Implications

Sullivan

Fisher

2014

Hematology/Oncology Clinics of North America

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From 1976 – 2010, the US FDA approved only two medications for the treatment of metastatic melanoma, dacarbazine and high-dose interleukin 2. Between 2011–13, four agents were approved (ipilimumab, vemurafenib, dabrafenib, trametinib) and other therapies have shown great promise in clinical trials. This startling progress has been made possible by the groundbreaking efforts of basic scientists and the vision and innovation of translational and clinical investigators. Fundamental discoveries such as the identification of oncogenic mutations in the majority melanomas, the elucidation of the molecular signaling resultant from these mutations, and the revelation that a number of cell surface molecules serve as regulators of immune activation, have all been instrumental to this progress. This chapter provides a summary of the molecular pathogenesis of melanoma by reviewing the relevant melanocyte biology and molecular signaling used by melanoma, describes the current efforts to target oncogene driven signaling, and presents the rationale for combining immune and molecular targeting.

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Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling

Cited by 23 publications

References 42 publications

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

PKD2 and PKD3 Promote Prostate Cancer Cell Invasion via uPA by Shifting Balance Between NF-κB and HDAC1

Targeting Mutant BRAF in Melanoma

Understanding the Biology of Melanoma and Therapeutic Implications

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