The protein kinase C super‐family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression

Yang, Chunsong; Melhuish, Tiffany A.; Spencer, A. Benjamin; Ni, Li; Hao, Yi; Jividen, Kasey; Harris, Thurl E.; Snow, Chelsi J.; Frierson, Henry F.; Wotton, David; Paschal, Bryce M.

doi:10.1002/pros.23400

Cited by 32 publications

(32 citation statements)

References 51 publications

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“…More distantly related members of the PKC superfamily like PKN1, PKN2 and PRKD3 (PKCυ) were shown to play an important role in prostate cancer motility [ 127 , 128 ], and inhibition of PKN1 has been shown to be an attractive therapeutic strategy [ 128 , 129 ]. On the other hand, another PKC superfamily member, PRKD1 (PKCµ), is inversely associated with prostate cancer malignancy [ 130 ], illustrating the complex role of the PKC superfamily in prostate cancer.…”

Section: Nf-κb Signaling Pathways In Prostate Cancersmentioning

confidence: 99%

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

Staal

Beyaert

2018

Cells

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Prostate cancer is a highly prevalent form of cancer that is usually slow-developing and benign. Due to its high prevalence, it is, however, still the second most common cause of death by cancer in men in the West. The higher prevalence of prostate cancer in the West might be due to elevated inflammation from metabolic syndrome or associated comorbidities. NF-κB activation and many other signals associated with inflammation are known to contribute to prostate cancer malignancy. Inflammatory signals have also been associated with the development of castration resistance and resistance against other androgen depletion strategies, which is a major therapeutic challenge. Here, we review the role of inflammation and its link with androgen signaling in prostate cancer. We further describe the role of NF-κB in prostate cancer cell survival and proliferation, major NF-κB signaling pathways in prostate cancer, and the crosstalk between NF-κB and androgen receptor signaling. Several NF-κB-induced risk factors in prostate cancer and their potential for therapeutic targeting in the clinic are described. A better understanding of the inflammatory mechanisms that control the development of prostate cancer and resistance to androgen-deprivation therapy will eventually lead to novel treatment options for patients.

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Section: Nf-κb Signaling Pathways In Prostate Cancersmentioning

confidence: 99%

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

Staal

Beyaert

2018

Cells

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“…First, the Serine/threonine-protein kinase N2 (PKN2), which plays a role in the regulation of cell cycle progression, actin cytoskeleton assembly, cell migration, cell adhesion, tumor cell invasion and transcription activation signaling processes. It was recently shown to be phosphorylated by the PI-3 Kinase pathway and implicated in prostate cancer progression (65). Second, the nuclear receptor binding protein (NRBP1), which is involved in subcellular ER-Golgi trafficking.…”

Section: Identification Of Resistance Markersmentioning

confidence: 99%

Integrative proteomic and phosphoproteomic profiling of prostate cell lines

Katsogiannou

Boyer

Valdeolivas

et al. 2019

Preprint

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BackgroundProstate cancer is a major public health issue, mainly because patients relapse after androgen deprivation therapy. Proteomic strategies, aiming to reflect the functional activity of cells, are nowadays among the leading approaches to tackle the challenges not only of better diagnosis, but also of unraveling mechanistic details related to disease etiology and progression. MethodsWe conducted here a large SILAC-based Mass Spectrometry experiment to map the proteomes and phosphoproteomes of four widely used prostate cell lines, namely PNT1A, LNCaP, DU145 and PC3, representative of different cancerous and hormonal status. ResultsWe identified more than 3000 proteins and phosphosites, from which we quantified more than 1000 proteins and 500 phosphosites after stringent filtering. Extensive exploration of this proteomics and phosphoproteomics dataset allowed characterizing housekeeping as well as cell-line specific proteins, phosphosites and functional features of each cell line. In addition, by comparing the sensitive and resistant cell lines, we identified protein and phosphosites differentially expressed in the resistance context. Further data integration in a molecular network highlighted the differentially expressed pathways, in particular migration and invasion, RNA splicing, DNA damage repair response and transcription regulation. ConclusionsOverall, this study proposes a valuable resource toward the characterization of proteome and phosphoproteome of four widely used prostate cell lines. † Equal Contribution Correspondence: anais.baudot@univ-amu.fr,

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“…PKN2 regulates epithelial bladder cells speed and directmovement during cell migration and tumor cell invasion [ 18 ]. In human prostate cancer cells, PKN2 contributes to motility pathways and influences differentiation during prostate cancer progression [ 19 ]. PKN2 is highly expressed in triple-negative breast cancer cells and is required to support the growth of cancer [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway

et al. 2018

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BackgroundProtein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor associated macrophages (TAMs) polarization in colon cancer has never been reported.MethodsPKN2 expression in human colon cancer tissues was examined with immunohistochemistry (IHC). M1/M2 macrophage signatures were evaluated by RT-PCR, IHC and flow cytometry. The effects of PKN2 on tumor growth and TAM polarization were investigated both in vitro and in vivo. PKN2 targeted cytokines/pathway were analyzed by gene expression analysis and further confirmed by PCR, luciferase assay or western blot. Correlations between PKN2 and transcriptional factors for IL4 and IL10 were confirmed by ChIP-qPCR. The catalytic activities of PKN2 and DUSP6 were determined by kinase activity assay. Interactions between PKN2 and DUSP6 were confirmed by Co-IP.ResultsThe expression of PKN2 in colon cancer cells predicted a favorable prognosis and was associated with low M2 macrophage content in human colon cancer tissues. PKN2 inhibited tumor growth in mice xenograft model and inhibited M2 phenotype polarization both in vitro and in vivo. Mechanistically, PKN2 suppresses the expression of IL4 and IL10 from colon cancer cells by inhibiting Erk1/2 phosphorylation, which is required for phosphorylation and binding of CREB and Elk-1 to the promoters of IL4 and IL10. DUSP6, which is phosphorylated and activated through direct association with PKN2, suppresses Erk1/2 activation.ConclusionsThe expression of PKN2 in colon cancer cells suppresses tumor associated M2 macrophage polarization and tumor growth. Targeting PKN2 signaling pathway may provide a potential therapeutic strategy for colon cancer.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0747-z) contains supplementary material, which is available to authorized users.

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The protein kinase C super‐family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression

Cited by 32 publications

References 51 publications

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

Inflammation and NF-κB Signaling in Prostate Cancer: Mechanisms and Clinical Implications

Integrative proteomic and phosphoproteomic profiling of prostate cell lines

PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway

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