Nutritional Limitation Sensitizes Mammalian Cells to GSK-3β Inhibitors and Leads to Growth Impairment

The serine/threonine kinase GSK-3 beta was initially described as a key enzyme involved in glucose metabolism, but it is now known to regulate a wide range of biological processes, including proliferation and apoptosis. We previously reported a transformation-dependent cell death induced by glucose limitation in K-ras-transformed NIH3T3. To address the mechanism of this phenomenon, we analyzed GSK-3 beta regulation in these cells in conditions of high versus low glucose availability. We found that glucose depletion caused a marked inhibition of GSK-3 beta through posttranslational mechanisms and that this inhibition was much less pronounced in normal cells. Further inhibition of GSK-3 beta with lithium chloride, combined with glucose shortage, caused specific activation of AMP-activated protein kinase and significant suppression of proliferation in transformed but not normal cells. The cooperative effect of lithium and low glucose availability on cell growth did not seem to depend exclusively on ras pathway activation because two human cell lines, A549 and MDA-MB-231, both harboring an activated ras gene, showed very different sensitivity to lithium. These findings thus provide a rationale to further analyze the biochemical bases for combined glucose deprivation and GSK-3 beta inhibition as a new approach to control transformed cell growth. (Am J Pathol 2011, 178:1814-1823; DOI: 10.1016/j.ajpath.2010.12.047)