Time-dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a.

Lowered availability of oxygen in the micro-environment of cells perturbs metabolic and signaling pathways. It affects proliferation, tissue morphology, and differentiation. Leukemia impairs maturation of hematopoietic progenitors: the immune system, healing, and erythropoiesis are weakened, thereby perturbing iron homeostasis and further lowering oxygen provision to tissues. Here, the time-dependent molecular consequences of sudden hypoxia were studied in the KG1a model of immature hematopoietic progenitors. The oxygen tension of KG1a cells was abruptly lowered from the experimentally usual ca. 20 to 1%. Growth and key hubs of signaling, metabolism, and iron homeostasis were monitored by a combination of immunological methods and functional assays. The collapse of oxygen availability stopped proliferation after one generation. The number of cells then remained approximately constant over several days, including after anaerobic changes in the culture medium. Lowered oxygen resulted in transient increase of the hypoxia-inducible factor 1α and of its REDD1 target, inhibition of mechanistic (or mammalian) target of rapamycin, decreased autophagy, altered cap-dependent translation, and minimal repression of the already weak oxidative phosphorylation. These adjustments did not trigger important cellular iron fluxes since the cells relied on their internal iron stores to survive. In conclusion, the response of the KG1a cells to stringent hypoxia is varied, with some established hypoxia-sensitive pathways exhibiting activation whereas others were unaffected. The results draw attention to the flexibility of the environmental adaptation of cancer cells. They suggest that thorough characterization of early leukemic blasts is warranted to propose informed treatments to patients.

Low-level cadmium doses do not jeopardize the insulin secretion pathway of ß-cell models until the onset of cell death.

BACKGROUND: Cadmium is an inescapable environmental pollutant that permeates the food chain and has been debatably associated with diabetes in humans. PURPOSE AND PROCEDURES: To probe the specific impact of low-level cadmium exposure on insulin production, largely sub-cytotoxic (50-500 nM) concentrations of cadmium chloride challenged the INS-1 and MIN6 rodent models of pancreatic ß-cells for the longest possible time, up to 4 days, before sub-culturing. MAIN FINDINGS: The concentration of detectable oxidants, the pattern of the actin cytoskeleton, the translocation of ß-catenin, the activity of protein phosphatases, calcium traffic, and the phosphorylation status of several key signaling nodes, such as AMP kinase and mitogen activated kinases including nuclear translocation of Extracellular signal-Regulated Kinase, were all insensitive to the applied very low cadmium doses. Accordingly, low-level cadmium exposure did not alter the insulin secretion ability, the functional hallmark of ß-cells, before the onset of cell death. CONCLUSIONS: These data define an operational toxicological threshold for these cellular models of ß-cells that should be useful to address insulin secretion and the diabetogenic effects of chronic low-level cadmium exposure in animal models and in humans.