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

摘要

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) 伪 in primary breast cancer growth, its role in the molecular pathways leading to metastasis has not been studied comprehensively. By treating mice with 伪V5-3, a novel peptide inhibitor selective for PKC伪, we were able to determine how PKC伪 regulates metastasis of mammary cancer cells using a syngeneic and orthotopic model. The primary tumor growth was not affected by 伪V5-3 treatment. However, the mortality rate was reduced and metastasis in the lung decreased by more than 90% in the 伪V5-3-treated mice relative to the control-treated mice. 伪V5-3 treatment reduced intravasation by reducing matrix metalloproteinase-9 activities. 伪V5-3 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. 伪V5-3 treatment caused no apparent toxicity in non-tumor-bearing na茂ve mice. Rather, inhibiting PKC伪 protected against liver damage and increased the number of immune cells in tumor-bearing mice. Importantly, 伪V5-3 showed superior efficacy relative to anti-CXCR4 antibody in reducing metastasis in vivo . Together, these data show that pharmacological inhibition of PKC伪 effectively reduces mammary cancer metastasis by targeting intravasation and lung seeding steps in the metastatic process and suggest that PKC伪-specific inhibitors, such as 伪V5-3, can be used to study the mechanistic roles of PKC伪 specifically and may provide a safe and effective treatment for the prevention of lung metastasis of breast cancer patients.