Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor family that is implicated in apoptosis, proliferation, migration, and inflammation. We describe our findings showing that TWEAK mediated the differentiation of RAW264.

1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is an effective agent for inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell lines. However, the extent of growth inhibition in these cell lines differs because LNCaP cells are much more responsive than PC-3 cells. Previous studies in LNCaP cells have shown that 1,25-(OH)(2)D(3) treatment results in G(0)/G(1) cell cycle accumulation, loss of Ki67 expression, and induction of apoptosis. One difference between the two cell lines is that PC-3 cells lack functional p53, a protein that plays roles both in cell cycle regulation and induction of apoptosis. In this study, the role of p53 in 1,25-(OH)(2)D(3) action was examined using the p53-negative PC-3 cells and a line of LNCaP cells, called LN-56, in which p53 function was shut off using a dominant negative p53 fragment. We found that treatment with 1,25-(OH)(2)D(3) extensively inhibits growth of LN-56 prostate cancer cells lacking p53, but in contrast to the parental LNCaP cells, the LN-56 cells recover rapidly. Moreover, in prostate cancer cells, the synergism between 1,25-(OH)(2)D(3) and 9-cis retinoic acid appears to be dependent on the presence of functional p53; however, 1,25-(OH)(2)D(3)-mediated induction of G(1) cell cycle accumulation and induction of apoptosis is not.

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among American men. It arises primarily from the epithelial secretory cells of the peripheral prostate gland; generally occurs as a multifocal disease within the prostate gland; and then preferentially metastasizes to lymph nodes, bone, lung, and brain. Localized disease can be treated relatively successfully by radical prostatectomy (Catalona and Smith, 1998). In contrast, treatments for metastatic prostate cancer, including androgen ablation, are initially effective, but the majority of patients relapse with androgen independent prostate cancer (Denis, 1998; Leewansangtong and Crawford, 1998). The incidence of prostate cancer and the lack of good, long-term treatments for metastatic disease highlight the need for new chemopreventive and chemotherapeutic treatments. As discussed below, active vitamin D metabolites and analogs of the active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), are candidates for these treatments. Vitamin DVitamin D is best known for its actions in regulating calcium levels and bone remodeling (reviewed in Brown et al, 1999), but recent studies highlight a role for vitamin D in the growth and differentiation of various cell types. It is synthesized in the epidermis by the conversion of its precursor, 7-dehydrocholesterol, into vitamin D 3 , a reaction catalyzed by the ultraviolet rays of sunlight. Subsequent hydroxylation reactions in the liver and kidney produce 1,25(OH) 2 D 3 (Holick, 1984). Levels of 1,25(OH) 2 D 3 are tightly regulated as excess 1,25(OH) 2 D 3 is inactivated by the enzyme 24-hydroxylase (Horst and Reinhardt, 1997).

No abstract

While the role of vitamin D in bone and mineral metabolism has been investigated extensively, the role of the vitamin D receptor in other tissues is less well understood. 1,25-Dihydroxyvitamin D3 (calcitriol) can act as a differentiating agent in normal tissues and can inhibit the growth of many cancer cell lines including LNCaP prostate cancer cells. We have shown previously that calcitriol causes LNCaP cell accumulation in the G0/G1 phase of the cell cycle. In this study, we demonstrate that calcitriol also induces apoptosis of LNCaP cells. The calcitriol-induced apoptosis is accompanied by a down-regulation of Bcl-2 and Bcl-X(L) proteins, both of which protect cells from undergoing apoptosis. Other proteins important in apoptotic control, Bax, Mcl-1, and Bcl-X(S), are unaffected by calcitriol treatment. We find that overexpression of Bcl-2 blocks calcitriol-induced apoptosis and reduces, but does not eliminate, calcitriol-induced growth inhibition. We conclude that both regulation of cell cycle and the apoptotic pathway are involved in calcitriol action in prostate cancer cells.