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

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

SUBMITTER: Kim J

PROVIDER: S-EPMC3767436 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Kim J J Thorne S H SH Sun L L Huang B B Mochly-Rosen D D

Oncogene 20100920 3

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 wa ...[more]

PMID: 20856202

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Project description:Carbon monoxide and nitric oxide are two of the most important vasoprotective mediators. Their downregulation observed during vascular dysfunction, which is associated with cancer progression, leads to uncontrolled platelet activation. Therefore, the aim of our studies was to improve vasoprotection and to decrease platelet activation during progression of mouse mammary gland cancer by concurrent use of CO and NO donors (CORM-A1 and DETA/NO, respectively). Methods: Mice injected intravenously with 4T1-luc2-tdTomato or orthotopically with 4T1 mouse mammary gland cancer cells were treated with CORM-A1 and DETA/NO. Ex vivo aggregation and activation of platelets were assessed in the blood of healthy donors and breast cancer patients. Moreover, we analyzed the compounds' direct effect on 4T1 mouse and MDA-MB-231 human breast cancer cells proliferation, adhesion and migration in vitro. Results: We have observed antimetastatic effect of combination therapy, which was only transient in orthotopic model. During early stages of tumor progression concurrent use of CORM-A1 and DETA/NO demonstrated vasoprotective ability (decreased endothelin-1, sICAM and sE-selectin plasma level) and downregulated platelets activation (decreased bound of fibrinogen and vWf to platelets) as well as inhibited EMT process. Combined treatment with CO and NO donors diminished adhesion and migration of breast cancer cells in vitro and inhibited aggregation as well as TGF-β release from breast cancer patients' platelets ex vivo. However, antimetastatic effect was not observed at a later stage of tumor progression which was accompanied by increased platelets activation and endothelial dysfunction related to a decrease of VASP level. Conclusion: The therapy was shown to have antimetastatic action and resulted in normalization of endothelial metabolism, diminution of platelet activation and inhibition of EMT process. The effect was more prominent during early stages of tumor dissemination. Such treatment could be applied to inhibit metastasis during the first stages of this process.

Project description:BackgroundPlant-based food medicine and functional foods have been consumed extensively due to their bioactive substances and health-beneficial effects. Vinegar is one of them due to its bioactivities, which confers benefits on human body. Our previous study has produced pineapple vinegar that is rich in gallic acid and caffeic acid via 2 steps fermentation. There are many evidences that show the effectiveness of these resources in inhibiting the proliferation and metastasis of the cancer cells through several mechanisms.MethodsFreeze-dried pineapple vinegar was evaluated for its in vitro apoptosis and metastasis inhibitory potential using MTT, cell cycle, Annexin V and scratch assays. The in vivo test using BALB/c mice challenged with 4?T1 cells was further investigated by pre-treating the mice with 0.08 or 2?ml/kg body weight of freshly-prepared pineapple vinegar for 28?days. The tumor weight, apoptotic state of cells in tumor, metastasis and immune response of the untreated and pineapple vinegar treatment group were evaluated and compared.ResultsFrom the in vitro study, an IC50 value of 0.25?mg/mL after 48?h of treatment was established. Annexin V/PI and scratch closure assays showed that pineapple vinegar induced 70% of cell population to undergo apoptosis and inhibited 30% of wound closure of 4?T1 cells. High concentration of pineapple vinegar (2?ml/kg body weight) led to the reduction of tumor weight and volume by 45%as compared to the untreated 4?T1-challenged mice. This effect might have been contributed by the increase of T cell and NK cells population associated with the overexpression of IL-2 andIFN-? cytokines and splenocyte cytotoxicity. Furthermore, fewer instances of metastasis events were recorded in the pineapple vinegar treatment group and this could be explained by the downregulation of inflammation related genes (iNOS, NF-kB and COX2), metastasis related genes (iCAM, VEGF and MMP9) and angeogenesis related genes (CD26, TIMP1, HGF, MMP3, IGFBP-1 and IGFBP-2).ConclusionThe ability of pineapple vinegar to delay cancer progression portrayed its potential as chemopreventive dietry intervention for cancer therapy.

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

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

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