Efficacy of Methionine-Restricted Diets on Cancers In Vivo.

Methionine (MET) dependence is the elevated requirement of cancer cells for MET. Cancer cells are arrested when MET is restricted in late S/G2 phase of the cell cycle. MET dependence may be the only known general metabolic defect in cancer. This chapter reviews the in vivo efficacy of dietary MET restriction (MR) to arrest human-cancer cell-line tumors and mouse tumors in nude mice. Human cancer xenografts in nude mice, when fed a MET-free diet, had greatly inhibited tumor growth. The body weight of mice on the MET-free diet was found to be maintainable by once-per-week administration of MET. These results suggested that MET dependence can be an important target for human cancer treatment. Yoshida sarcoma in nude mice on a MET-depleted diet regressed. MET depletion resulted in the extended survival of the tumor-bearing mice. These experiments are a prelude to further clinical studies of the efficacy of MR diets on cancer patients.

Mullerian Inhibiting Substance induces NFkB signaling in breast and prostate cancer cells.

The MIS type II receptor is expressed at high levels in the Mullerian duct and in Sertoli cells and granulosa cells of the embryonic and adult gonads. The presence of MIS type II and type I receptors in tissues and cell lines derived from breast and prostate suggests that the prostate and mammary glands may be additional targets for MIS action. In both breast and prostate cancer cells, MIS activated NFkB DNA binding activity and induced IEX-1, an immediate early gene which regulates cell growth and apoptosis. Exposure of cells to MIS inhibited growth by increasing the fraction of cells in the G1 phase of the cell cycle and by inducing apoptosis. These results suggest that MIS may be a putative mediator of growth regulatory signals in the breast and prostate.

Mullerian inhibiting substance promotes interferon gamma-induced gene expression and apoptosis in breast cancer cells.

This report demonstrates that in addition to interferons and cytokines, members of the TGF beta superfamily such as Mullerian inhibiting substance (MIS) and activin A also regulate IRF-1 expression. MIS induced IRF-1 expression in the mammary glands of mice in vivo and in breast cancer cells in vitro and stimulation of IRF-1 by MIS was dependent on activation of the NF kappa B pathway. In the rat mammary gland, IRF-1 expression gradually decreased during pregnancy and lactation but increased at involution. In breast cancer, the IRF-1 protein was absent in 13% of tumors tested compared with matched normal glands. Consistent with its growth suppressive activity, expression of IRF-1 in breast cancer cells induced apoptosis. Treatment of breast cancer cells with MIS and interferon gamma (IFN-gamma) co-stimulated IRF-1 and CEACAM1 expression and synergistic induction of CEACAM1 by a combination of MIS and IFN-gamma was impaired by antisense IRF-1 expression. Furthermore, a combination of IFN-gamma and MIS inhibited the growth of breast cancer cells to a greater extent than either one alone. Both reagents alone significantly decreased the fraction of cells in the S-phase of the cell cycle, an effect not enhanced when they were used in combination. However, MIS promoted IFN-gamma-induced apoptosis demonstrating a functional interaction between these two classes of signaling molecules in regulation of breast cancer cell growth.

Mullerian-inhibiting substance regulates NF-kappa B signaling in the prostate in vitro and in vivo.

Mullerian-inhibiting substance (MIS) is a member of the transforming growth factor beta superfamily, a class of molecules that regulates growth, differentiation, and apoptosis in many cells. MIS type II receptor in the Mullerian duct is temporally and spatially regulated during development and becomes restricted to the most caudal ends that fuse to form the prostatic utricle. In this article, we have demonstrated MIS type II receptor expression in the normal prostate, human prostate cancer cell lines, and tissue derived from patients with prostate adenocarcinomas. MIS induced NF-kappaB DNA binding activity and selectively up-regulated the immediate early gene IEX-1S in both androgen-dependent and independent human prostate cancer cells in vitro. Dominant negative IkappaBalpha expression ablated both MIS-induced increase of IEX-1S mRNA and inhibition of growth, indicating that activation of NF-kappaB signaling was required for these processes. Androgen also induced NF-kappaB DNA binding activity in prostate cancer cells but without induction of IEX-1S mRNA, suggesting that MIS-mediated increase in IEX-1S was independent of androgen-mediated signaling. Administration of MIS to male mice induced IEX-1S mRNA in the prostate in vivo, suggesting that MIS may function as an endogenous hormonal regulator of NF-kappaB signaling and growth in the prostate gland.