No abstract

Physical inactivity and high-fat diet, especially high saturated fat containing diet are established risk factors for breast cancer that are amenable to intervention. High-fat diet has been shown to induce tumor growth and metastasis by alteration of inflammation but steady exercise has anti-tumorigenic effects. However, the mechanisms underlying the effects of physical activity on high-fat diet stimulated breast cancer initiation and progression are currently unclear. In this study, we examined how the intensity of physical activity influences high fat diet-stimulated breast cancer latency and progression outcomes, and the possible mechanisms behind these effects. Five-week-old female Balb/c mice were fed either a control diet or a high-fat diet for 8 weeks, and then 4T1 mouse mammary tumor cells were inoculated into the mammary fat pads. Exercise training occurred before tumor cell injection, and tumor latency and tumor volume were measured. Mice with a high-fat diet and low-intensity exercise (HFLE) had a longer tumor latency period, slower tumor growth, and smaller tumor volume in the final tumor assessment compared with the control, high-fat diet control (HFDC), and high-fat diet with moderate-intensity exercise (HFME) groups. Steady low- and moderate-intensity exercise had no effect on cell proliferation but induced apoptosis by activating caspase-3 through the alteration of Bcl-2, Bcl-xL, and Bax expression. Furthermore, steady exercise reduced M2 macrophage polarization in breast tumor tissue, which has been linked to tumor growth. The myokine, myostatin, reduced M2 macrophage polarization through the inhibition of the JAK-STAT signaling pathway. These results suggest that steady low-intensity exercise could delay breast cancer initiation and growth and reduce tumor volume through the induction of tumor cell apoptosis and the suppression of M2 macrophage polarization.

The growing incidence of prostate cancer and the traditional use of Rubus coreanus Miquel (RCM) for prostate health led us to compare RCM extracts and to test their efficacy in inhibiting the growth of prostate cancer cells differing in androgen dependency. Ethanol extracts of unripe RCM (EUR) were more effective in reducing cell viability than water extracts or ripe RCM. EUR-induced growth inhibition, as indicated by significant reductions in numbers of proliferating cells and decreases in the protein levels of proliferating cell nuclear antigen (PCNA), cyclin D1 and CDK4, was greater in the androgen-dependent LNCaP cells than in the androgen-independent DU145 cells. EUR also induced mitochondrial-mediated apoptosis in prostate cancer cells by reducing Bcl-2 and Bcl-(X)L levels, but increased Bax levels. Nevertheless, the LNCaP cells were more sensitive to EUR-induced apoptosis and displayed sub-G1 and late apoptotic cell populations, whereas the DU145 cells did not. Our findings suggest that EUR suppresses the growth of prostate cancer cells by anti-proliferative and/or pro-apoptotic effects, and that these effects are stronger in androgen-dependent cells.

Rubus coreanus Miquel (RCM) is used to promote prostate health and has been shown to have anti-oxidant and anti-carcinogenic activities. However, the effects and mechanisms of RCM on prostate cancer metastasis remain unclear. PC-3 and DU 145 cells were treated with ethanol or water extract of unripe or ripe RCM and examined for cell invasion, migration, and matrix metalloproteinases (MMPs) activity and expression. Phosphoinositide 3-kinase (PI3K) and Akt activities were examined. Unripe RCM extracts exerted significant inhibitory effects on cell migration, invasion, and MMPs activities. A significant reduction in MMPs activities by unripe RCM ethanol extract treatment (UE) was associated with reduction of MMPs expression and induction of tissue inhibitors of metalloproteinases (TIMPs) expression. Furthermore, PI3K/Akt activity was diminished by UE treatment. In this study, we demonstrated that UE decreased metastatic potential of prostate cancer cells by reducing MMPs expression through the suppression of PI3K/Akt phosphorylation, thereby decreasing MMP activity and enhancing TIMPs expression.

The growing incidence of prostate cancer and the traditional use of Rubus coreanus Miquel (RCM) for prostate health led us to compare RCM extracts and to test their efficacy in inhibiting the metastasis of prostate cancer cells. DU145 and PC‐3 cells were treated with unripe RCM ethanol extract (UE), unripe RCM water extract (UH), ripe RCM ethanol extract (RE), or ripe RCM water extract (RH) at concentration of 100 μg/ml for 24 h then matrix metalloproteinase‐2 (MMP‐2), MMP‐9, membrane type 1‐MMP (MT1‐MMP), MT2‐MMP, tissue inhibitors of metalloproteinase‐1 (TIMP‐1), and TIMP‐2 expressions were assessed by western blot and real‐time polymerase chain reaction (PCR). Invasion and wound healing assays were also performed. UE and UH treatment significantly reduced wound healing in a dose‐dependent manner. Furthermore, UE and UH treatment decreased MMP‐2 and ‐9 mRNA and protein expressions but increased TIMP‐1 and TIMP‐2 mRNA and protein expressions. These results suggest that unripe RCM inhibits migration and invasion of prostate cancer cells by reducing MMPs and inducing TIMPs expression. This research was supported financially by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Project No. 2009‐0068227)