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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
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Protein kinase C is inhibited by bisphosphonates in prostate cancer PC-3 cells

Yoshiki Tatsuda1, Kazuhiro Iguchi, Shigeyuki Usui

  • 1Laboratory of Pharmaceutics, Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi, Gifu, Gifu 502-8585, Japan.

European Journal of Pharmacology
|November 12, 2009
PubMed

Insights

Bisphosphonates, like pamidronate, inhibit protein kinase C (PKC) expression and activity in prostate cancer cells. This PKC inhibition by bisphosphonates is a key mechanism reducing tumor bone metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Bisphosphonates are utilized to prevent bone metastasis in cancers.
  • Protein kinase C (PKC) is implicated in cancer progression and metastasis.

Purpose of the Study:

  • To investigate the mechanism by which bisphosphonates inhibit prostate cancer bone metastasis.
  • To determine the effect of bisphosphonates on protein kinase C (PKC) expression and activity.

Main Methods:

  • Prostate cancer PC-3 cells were treated with pamidronate.
  • PKC protein expression, activity, and urokinase-type plasminogen activator (uPA) levels were assessed.
  • The role of the mevalonate pathway was evaluated.
  • PKC inhibitors and activators were used to study uPA regulation.

Main Results:

  • Pamidronate significantly reduced PKC protein expression and activity in PC-3 cells, specifically targeting PKCalpha and PKCzeta.
  • The observed inhibition of PKC was independent of the mevalonate pathway.
  • Bisphosphonate treatment led to decreased expression of urokinase-type plasminogen activator (uPA), a critical metastasis-associated protein.
  • PKC inhibition was linked to the suppression of uPA expression.

Conclusions:

  • Bisphosphonates suppress protein kinase C (PKC) expression and activity in prostate cancer cells.
  • This suppression of PKC is a novel mechanism contributing to the anti-metastatic effects of bisphosphonates in bone.
  • The inhibition of uPA expression, mediated by PKC inhibition, is a significant factor in bisphosphonates' ability to reduce tumor bone metastasis.

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