A novel cysteine cathepsin inhibitor yields macrophage cell death and mammary tumor regression.

Although cysteine cathepsins have been identified as key regulators of cancer growth, their specific role in tumor development remains unclear. Recent studies have shown that high activity levels of tumor cathepsins are primarily a result of increased cathepsin activity in cancer-promoting tumor-associated macrophages (TAMs). To further investigate the role of cysteine cathepsin activity in normal and polarized macrophages, we established in vitro and in vivo models of macrophage differentiation and polarization and used a novel cysteine cathepsin inhibitor, GB111-NH2, to block the activity of cathepsins B, L and S. Here we show that in vitro, cysteine cathepsin inhibition yields both apoptosis and proliferation of macrophages, owing to increased oxidative stress. Proteomic analysis of cathepsin- inhibited macrophages demonstrates inhibition of autophagy, suggesting a likely cause of elevated reactive oxygen species (ROS) levels. In vivo models of mammary cancer further show that cathepsin inhibition yields TAM death owing to increased ROS levels. Strikingly, apoptosis in TAMs yields a seemingly cell non-autonomous death of neighboring cancer cells, and regression of the primary growth. These results show that cysteine cathepsin inhibitors can specifically trigger macrophage cell death and may function as an effective anticancer therapy in tumors with high levels of TAMs.

Living under a "dormant" canopy: a molecular acclimation mechanism of the desert plant Retama raetam.

Desert plants are exposed to a combination of environmental stress conditions, including low water availability, extreme temperature fluctuations, high irradiance and nutrient deprivation. Studying desert plants within their natural habitat may therefore reveal novel mechanisms and strategies that enable plants to resist stressful conditions. We studied the acclimation of Retama raetam, an evergreen stem-assimilating desert plant, to growth within an arid dune ecosystem. Retama raetam contained two different populations of stems: those of the upper canopy, exposed to direct sunlight, and those of the lower canopy, protected from direct sunlight. During the dry season, stems of the upper canopy contained a very low level of a number of essential proteins, including the large and small subunits of rubisco, ascorbate peroxidase and the D1 subunit of the reaction centre of photosystem II. However, RNA encoding these proteins was present; cytosolic transcripts were associated with polysomes, while chloroplastic transcripts were not. Upon water application, as well as following the first rainfall of the season, these "photosynthetically suppressed" stems recovered and accumulated essential proteins within 6-24 h. In contrast, stems of the lower canopy contained the essential proteins throughout the dry season. We suggest that R. raetam uses an acclimation strategy of "partial plant dormancy" in order to survive the dry season. "Dormancy", as evident by the post-transcriptional suppression of gene expression, as well as the suppression of photosynthesis, was induced specifically in stems of the upper canopy which protect the lower canopy by shading.