Prostate cancer proliferation mechanisms

Presently it is under Phase 1 clinical trials for breast and prostate cancer. It has shown inhibitory activity for cancer cell growth and proliferation. The mechanism of anticancer activity is believed to be the... 

CaSR may also influence the proliferative and apoptotic status of the cells indirectly via modulation of cell volume homeostasis. Indeed, stimulation of CaSR in human epithelial cells induces upregulation of volume-regulated anion channels (VRAC) via a G protein-mediated increase in intracellular cAMP (Shimizu, et al., 2000). Proliferation and apoptosis are associated with essential volume perturbations [e.g., (Lang, et al., 2000)] and VRAC, a key component of homeostatic volume regulation, has been directly implicated in proliferation (Chen, et al., 2002, Doroshenko, et al., 2001, Shen, et al., 2000, Wang, et al., 2002) and apoptosis (Lemonnier, et al., 2004, Okada, et al., 2001, Okada, et al., 2006, Shen, et al., 2002). Consequently, extracellular Ca2+ may affect carcinogenesis via the CaSR-VRAC-cell volume links. The Ca2+ -permeable store-operated channel (SOC) is directly and functionally coupled to VRAC in an androgen-dependent LNCaP human prostate cancer epithelial cell line (Lemonnier, et al., 2002), evidence for another, CaSR-unrelated, potential mechanism for extracellular Ca2+ involvement in proliferative and apoptotic events. 

The mechanisms of action of steroid hormones on lymphoid, mammary, and prostatic cancer have been partially clarified. Specific cell surface receptors have been identified for estrogen, progesterone, corticosteroids, and androgens in neoplastic cells in these tissues. As in normal cells, steroid hormones also form an intracellular steroid-receptor complex that ultimately binds directly to nuclear proteins associated with DNA to activate transcription of a broad range of cellular genes involved in cell growth and proliferation (see Chapter 39 Adrenocorticosteroids Adrenocortical Antagonists). 

One possible integrator of these 12(S)-HETE signaling mechanisms in tumor cells is the pleiotropic transcription factor NE-kB, which plays an important role in the control of cell proliferation and apoptosis. Using PC-3 prostate cancer cells, we have shown that either overexpression of the platelet-type 12-LOX or exogenously added 12(S)-HETE activates NF-kB (Kandouz et al.,... 

Lycopene in combination with vitamin E or vitamin D has been reported to potentiate inhibition of cancer cell growth. A synergistic effect was observed when physiologically relevant concentrations of a-tocopherol and lycopene were studied in various prostate cancer cell lines. Lycopene, in itself, was not a potent inhibitor of prostate carcinoma cell proliferation however, up to 90% growth inhibition was reported with the a-tocopherol and lycopene combined treatment. This synergistic effect was not shared by p-tocopherol, ascorbic acid, or probucol, indicating a nonantioxidant mechanism to be the basis of the finding. 

Palombo and colleagues (40) investigated the effects of different types and concentrations of CLA and linoleic acid on colorectal and prostate cancer (PC3) cell proliferation and cytotoxicity. Linoleic add was without effect at all concentrations and in all cells, which appears to be a consensus in all reports. PC3 cells were the least sensitive to CLA treatment of the cells studied. These authors also found an induction of a homogeneous caspase activity (caspases 2,3,6-10) indicative of an induction of apoptosis, but they did not investigate other underlying cellular mechanisms to explain their findings. 

Given the positive correlation between the incidence of prostatic cancer and consumption of high fat diets, a possible mechanism of enhancement could be similar to that occurring in the mammary gland. Dietary fats can modify hormonally dependent processes as well as specific membrane responses leading to increased cell proliferation (NAS, 1982 Welsch and Aylsworth, 1983). How-... 

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