Protein kinase D1 stimulates proliferation and enhances tumorigenesis of MCF-7 human breast cancer cells through a MEK/ERK-dependent signaling pathway

Karam, Manale; Legay, Christine; Auclair, Christian; Ricort, Jean‐Marc

doi:10.1016/j.yexcr.2012.01.001

Cited by 43 publications

(59 citation statements)

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“…Moreover, the selective MAPK/ERK signaling pathway inhibitor U0126 attenuated the chemoresistance of MCF7 cells resulting from BMP6 knockdown. In fact, our previous and other various studies have also confirmed that ERK signaling pathway activation is involved in cancer cell chemoresistance (23,29). ERK signaling pathway-modulated mdr-1 gene expression was also confirmed in various studies (30,31).…”

Section: Discussionsupporting

confidence: 71%

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Lian

Liu

et al. 2013

Oncology Reports

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Abstract. Previous studies indicate that bone morphogenetic protein (BMP) 6 is involved in breast cancer development and progression. However, the mechanism underlying the role of BMP6 in breast cancer cell proliferation, differentiation and chemoresistance remains unknown. In this study, we confirmed that BMP6 expression was downregulated in breast cancer tissues compared with the adjacent normal breast tissues. We further demonstrated that the downregulation of BMP6 was correlated with the estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade and enhanced proliferation (Ki67 proliferation index). In vitro functional experiments showed that the suppression of BMP6 expression by a specific small hairpin (sh)RNA vector led to increased proliferation in the MCF7 breast cancer cell line. Furthermore, knockdown of BMP6 in MCF7 cells enhanced the chemoresistance to doxorubicin by upregulation of mdr-1/P-gp expression and activation of the ERK signaling pathway. Taken together, our data suggest that BMP6 plays a critical role in breast cancer cell aberrant proliferation and chemoresistance and may serve as a novel diagnostic biomarker or therapeutic target for breast cancer.

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Section: Discussionsupporting

confidence: 71%

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Lian

Liu

et al. 2013

Oncology Reports

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“…Finally, despite its failure to induce the expression of functional E-cadherin, PKD1 knockdown alone strongly altered anchorage-independent growth and migration of metastatic melanoma cells, probably by regulating signaling pathways such as extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and nuclear factor-kappa B (NFκB), as previously described in hormone-positive breast cancer [72, 73] and pancreatic cancer [74, 75]. …”

Section: Discussionmentioning

confidence: 83%

Protein kinase C inhibitor Gö6976 but not Gö6983 induces the reversion of E- to N-cadherin switch and metastatic phenotype in melanoma: identification of the role of protein kinase D1

et al. 2017

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BackgroundMelanoma is a highly metastatic type of cancer that is resistant to all standard anticancer therapies and thus has a poor prognosis. Therefore, metastatic melanoma represents a significant clinical problem and requires novel and effective targeted therapies. The protein kinase C (PKC) family comprises multiple isoforms of serine/threonine kinases that possess distinct roles in cancer development and progression. In this study, we determined whether inhibition of PKC could revert a major process required for melanoma progression and metastasis; i.e. the E- to N-cadherin switch.MethodsThe cadherin switch was analyzed in different patient-derived primary tumors and their respective metastatic melanoma cells to determine the appropriate cellular model (aggressive E-cadherin-negative/N-cadherin-positive metastasis-derived melanoma cells). Next, PKC inhibition in two selected metastatic melanoma cell lines, was performed by using either pharmacological inhibitors (Gö6976 and Gö6983) or stable lentiviral shRNA transduction. The expression of E-cadherin and N-cadherin was determined by western blot. The consequences of cadherin switch reversion were analyzed: cell morphology, intercellular interactions, and β-catenin subcellular localization were analyzed by immunofluorescence labeling and confocal microscopy; cyclin D1 expression was analyzed by western blot; cell metastatic potential was determined by anchorage-independent growth assay using methylcellulose as semi-solid medium and cell migration potential by wound healing and transwell assays.ResultsGö6976 but not Gö6983 reversed the E- to N-cadherin switch and as a consequence induced intercellular interactions, profound morphological changes from elongated mesenchymal-like to cuboidal epithelial-like shape, β-catenin translocation from the nucleus to the plasma membrane inhibiting its oncogenic function, and reverting the metastatic potential of the aggressive melanoma cells. Comparison of the target spectrum of these inhibitors indicated that these observations were not the consequence of the inhibition of conventional PKCs (cPKCs), but allowed the identification of a novel serine/threonine kinase, i.e. protein kinase Cμ, also known as protein kinase D1 (PKD1), whose specific inhibition allows the reversion of the metastatic phenotype in aggressive melanoma.ConclusionIn conclusion, our study suggests, for the first time, that while cPKCs don’t embody a pertinent therapeutic target, inhibition of PKD1 represents a novel attractive approach for the treatment of metastatic melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3007-5) contains supplementary material, which is available to authorized users.

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“…PKD1 contributes to breast cancer cell proliferation (10), but inhibits the invasive phenotype (11,12). This is mediated by inhibition of epithelial-to-mesenchymal transition (EMT) through phosphorylation of Snail (13–16), down-regulation of the expression of several matrix metalloproteinases (MMPs), and negative-regulation of F-actin reorganization at the leading edge at multiple levels (12,13,17,18).…”

Section: Introductionmentioning

confidence: 99%

Effective Targeting of Estrogen Receptor–Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101

Borgés

Perez

Thompson

et al. 2015

Molecular Cancer Therapeutics

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Invasive ductal carcinomas (IDCs) of the breast are associated with altered expression of hormone receptors (HR), amplification or overexpression of HER2, or a triple-negative phenotype. The most aggressive cases of IDC are characterized by a high proliferation rate, a great propensity to metastasize and their ability to resist to standard chemotherapy, hormone therapy or HER2 targeted therapy. Using progression tissue microarrays we here demonstrate that the serine/threonine kinase Protein Kinase D3 (PKD3) is highly up-regulated in estrogen receptor (ER)-negative tumors. We identify direct binding of the estrogen receptor to the PRKD3 gene promoter as a mechanism of inhibition of PKD3 expression. Loss of ER results in upregulation of PKD3 leading to all hallmarks of aggressive IDC, including increased cell proliferation, migration and invasion. This identifies ER-negative breast cancers as ideal for treatment with the PKD inhibitor CRT0066101. We show that similar to a knockdown of PKD3, treatment with this inhibitor targets all tumorigenic processes in vitro and decreases growth of primary tumors and metastasis in vivo. Our data strongly support the development of PKD inhibitors for clinical use for ER-negative breast cancers, including the triple-negative phenotype.

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Protein kinase D1 stimulates proliferation and enhances tumorigenesis of MCF-7 human breast cancer cells through a MEK/ERK-dependent signaling pathway

Cited by 43 publications

References 42 publications

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Protein kinase C inhibitor Gö6976 but not Gö6983 induces the reversion of E- to N-cadherin switch and metastatic phenotype in melanoma: identification of the role of protein kinase D1

Effective Targeting of Estrogen Receptor–Negative Breast Cancers with the Protein Kinase D Inhibitor CRT0066101

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