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Regulation of inside-out β1-integrin activation by CDCP1.

Sara G Pollan1, Fangjin Huang1, Jamie M Sperger2

  • 1Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Oncogene
|March 8, 2018
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Summary
This summary is machine-generated.

Reduced expression of CDCP1 in prostate cancer promotes metastasis by disrupting cell adhesion and promoting non-adherent cell growth. This study uncovers a new mechanism involving CDK5 regulation impacting integrin activity.

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Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor metastasis is regulated by cell adhesion molecules like β1-integrin.
  • Cub-Domain Containing Protein-1 (CDCP1) is a transmembrane glycoprotein involved in cell adhesion.
  • Altered CDCP1 expression is linked to metastatic progression in various cancers.

Purpose of the Study:

  • Investigate the role of CDCP1 in castrate-resistant prostate cancer (CRPC) progression.
  • Elucidate the mechanism by which CDCP1 loss affects cell adhesion, proliferation, and tumor growth.
  • Identify the molecular pathway linking CDCP1 to β1-integrin activation and CDK5 activity.

Main Methods:

  • Reduced CDCP1 expression was analyzed in patient samples (primary tumors, CTCs, metastases).
  • CDCP1 function was assessed in prostate cancer cell lines (DU145, PC3) using silencing techniques.
  • Tumor growth was evaluated in mouse models.
  • Molecular mechanisms involving CDK5, c-SRC, PKCδ, and β1-integrin were investigated through phosphorylation site analysis.

Main Results:

  • CDCP1 expression is reduced in high-grade CRPC, circulating tumor cells, and metastases.
  • CDCP1 silencing increased non-adherent cell proliferation, anchorage-independent growth, and tumor formation in mice.
  • Loss of CDCP1 diminished cell adhesion and migration by impairing β1-integrin activation.
  • CDCP1 loss reduces CDK5 activity via c-SRC and PKCδ-mediated phosphorylation of CDK5R1/p35 and CDK5.

Conclusions:

  • Reduced CDCP1 expression is associated with aggressive prostate cancer and promotes metastasis.
  • CDCP1 loss dysregulates CDK5 activity, leading to impaired β1-integrin activation and enhanced non-adherent cell behavior.
  • This pathway represents a novel mechanism contributing to prostate cancer vascular dissemination.