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Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model

Oncogene volume 30, pages 323–333 (2011)Cite this article

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Abstract

Metastasis is the major reason for breast cancer-related deaths. Although there is a host of indirect evidence for a role of protein kinase C (PKC) α in primary breast cancer growth, its role in the molecular pathways leading to metastasis has not been studied comprehensively. By treating mice with αV5-3, a novel peptide inhibitor selective for PKCα, we were able to determine how PKCα regulates metastasis of mammary cancer cells using a syngeneic and orthotopic model. The primary tumor growth was not affected by αV5-3 treatment. However, the mortality rate was reduced and metastasis in the lung decreased by more than 90% in the αV5-3-treated mice relative to the control-treated mice. αV5-3 treatment reduced intravasation by reducing matrix metalloproteinase-9 activities. αV5-3 treatment also reduced lung seeding of tumor cells and decreased cell migration, effects that were accompanied by a reduction in nuclear factor kappa B activity and cell surface levels of the CXCL12 receptor, CXCR4. αV5-3 treatment caused no apparent toxicity in non-tumor-bearing naïve mice. Rather, inhibiting PKCα protected against liver damage and increased the number of immune cells in tumor-bearing mice. Importantly, αV5-3 showed superior efficacy relative to anti-CXCR4 antibody in reducing metastasis in vivo. Together, these data show that pharmacological inhibition of PKCα effectively reduces mammary cancer metastasis by targeting intravasation and lung seeding steps in the metastatic process and suggest that PKCα-specific inhibitors, such as αV5-3, can be used to study the mechanistic roles of PKCα specifically and may provide a safe and effective treatment for the prevention of lung metastasis of breast cancer patients.

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Acknowledgements

We thank Dr Erinn Bruno Rankin in Dr Amato Giaccia's lab at the Department of Radiation Oncology at Stanford University for generous technical support and Dr Adrienne Gordon for critical reading of the paper. This work was supported in part by PHS Grant Number CA09151, awarded by the National Cancer Institute, DHHS (to JK).

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  1. J Kim and S H Thorne: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA, USA

    J Kim, L Sun & D Mochly-Rosen

  2. Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA, USA

    S H Thorne

  3. Division of Surgical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    S H Thorne & B Huang

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  1. J Kim
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Correspondence to D Mochly-Rosen.

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DMR is the founder of KAI Pharmaceuticals. However, none of the work at her laboratory was supported by the company and the company had no access to information about unpublished research. The remaining authors declare no conflict of interest.

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Kim, J., Thorne, S., Sun, L. et al. Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene 30, 323–333 (2011). https://doi.org/10.1038/onc.2010.415

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