CrkL regulates SDF-1-induced breast cancer biology through balancing Erk1/2 and PI3K/Akt pathways

Med Oncol. 2015 Jan;32(1):411. doi: 10.1007/s12032-014-0411-z. Epub 2014 Dec 5.

Abstract

The adapter protein CrkL is required for regulating the malignant potential of human cancers. However, the regulatory mechanisms of CrkL on the stromal cell-derived factor 1 (SDF-1)/CXCR4 signaling pathways in breast cancer are not well characterized. Here, CXCR4 and CrkL proteins were tested in breast cancer cell lines and 60 primary breast cancer tissues. In vitro, the roles of CrkL in SDF-1-induced MDA-MB-231 cell cycle, invasion and migration were investigated. In the present study, CXCR4 and CrkL were highly expressed in MCF-7, MDA-MB-231, MDA-MB-231HM MDA-MB-468 and tumor tissues (80 and 60 %, respectively) and closely correlated with lymph node metastasis. In vitro studies revealed that SDF-1 induced the activation of CrkL, Erk1/2, Akt and matrix metallopeptidase 9 (MMP9) in MDA-MB-231 cells. The si-CrkL treatment significantly down-regulated the phosphorylated Erk1/2 (p-Erk1/2) and MMP9, but up-regulated p-Akt, compared with control. Importantly, wound-healing and transwell invasion assays showed that si-CrkL significantly impaired the wound closure and inhibited the SDF-1-induced invasion; similarly, flow cytometry showed that si-CrkL affected cell cycle. In conclusion, these results suggest that CrkL plays a regulatory role in the SDF-1-induced Erk1/2 and PI3K/Akt pathways and further managed the invasion and migration of breast cancer cells. Thus, CrkL may be recommended as an interesting therapeutic target for breast cancer.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adult
  • Aged
  • Blotting, Western
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Chemokine CXCL12 / metabolism
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System / physiology
  • Middle Aged
  • Neoplasm Invasiveness / pathology
  • Nuclear Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering
  • Receptors, CXCR4 / metabolism
  • Signal Transduction / physiology*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • CRKL protein
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Nuclear Proteins
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt