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

Manale Doldur, Christine Legay, Christian Auclair, Jean Marc Ricort

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Protein kinase D1, PKD1, is a novel serine/threonine kinase whose altered expression and dysregulation in many tumors as well as its activation by several mitogens suggest that this protein could regulate proliferation and tumorigenesis. Nevertheless, the precise signaling pathways used are still unclear and the potential direct role of PKD1 in tumor development and progression has not been yet investigated. In order to clarify the role of PKD1 in cell proliferation and tumorigenesis, we studied the effects of PKD1 overexpression in a human adenocarcinoma breast cancer cell line, MCF-7 cells. We demonstrated that overexpression of PKD1 specifically promotes MCF-7 cell proliferation through accelerating G0/G1 to S phase transition of the cell cycle. Moreover, inhibition of endogenous PKD1 significantly reduced cell proliferation. Taken together, these results clearly strengthen the regulatory role of PKD1 in cell growth. We also demonstrated that overexpression of PKD1 specifically diminished serum- and anchorage-dependence for proliferation and survival in vitro and allowed MCF-7 cells to form tumors in vivo. Thus, all these data highlight the central role of PKD1 in biological processes which are hallmarks of malignant transformation. Analysis of two major signaling pathways implicated in MCF-7 cell proliferation showed that PKD1 overexpression significantly increased ERK1/2 phosphorylation state without affecting Akt phosphorylation. Moreover, PKD1 overexpression-stimulated cell proliferation and anchorage-independent growth were totally impaired by inhibition of the MEK/ERK kinase cascade. However, neither of these effects was affected by blocking the PI 3-kinase/Akt signaling pathway. Thus, the MEK/ERK signaling appears to be a determining pathway mediating the biological effects of PKD1 in MCF-7 cells. Taken together, all these data demonstrate that PKD1 overexpression increases the aggressiveness of MCF-7 breast cancer cells through enhancing their oncogenic properties and would, therefore, define PKD1 as a potentially new promising anti-tumor therapeutic target.

Original languageEnglish
Pages (from-to)558-569
Number of pages12
JournalExperimental Cell Research
Volume318
Issue number5
DOIs
Publication statusPublished - 10 Mar 2012
Externally publishedYes

Fingerprint

Mitogen-Activated Protein Kinase Kinases
MCF-7 Cells
Protein Kinases
Carcinogenesis
Cell Proliferation
Breast Neoplasms
Neoplasms
Phosphorylation
MAP Kinase Kinase Kinases
Biological Phenomena
Protein-Serine-Threonine Kinases
Phase Transition
Growth
Phosphatidylinositol 3-Kinases
S Phase
Mitogens
Cell Cycle
Adenocarcinoma
Cell Line
Survival

Keywords

  • Breast cancer
  • Proliferation
  • Protein kinase D1
  • Signal transduction
  • Tumorigenesis

ASJC Scopus subject areas

  • Cell Biology

Cite this

Protein kinase D1 stimulates proliferation and enhances tumorigenesis of MCF-7 human breast cancer cells through a MEK/ERK-dependent signaling pathway. / Doldur, Manale; Legay, Christine; Auclair, Christian; Ricort, Jean Marc.

In: Experimental Cell Research, Vol. 318, No. 5, 10.03.2012, p. 558-569.

Research output: Contribution to journalArticle

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