Lactic Acidosis Triggers Starvation Response with Paradoxical Induction of TXNIP through MondoA

Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the “anti-Warburg” metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers

The Leiognathus splendens complex (Perciformes: Leiognathidae) with the description of a new species, Leiognathus kupanensis Kimura and Peristiwady

Taxonomic analysis of a group of morphologically similar ponyfishes (Perciformes: Leiognathidae) establishes the Leiognathus splendens complex comprising four valid species: L. jonesi James, 1971, widely distributed in the Indo-West Pacific, from Mauritius to Papua New Guinea, north to Hainan I. (China), and south to Brisbane, Australia; L. kupanensis sp. nov., currently known only from Kupang, Timor, Indonesia; L. rapsoni Munro, 1964, currently known only from India, Indonesia, and Papua New Guinea, and L. splendens Cuvier, 1829, widely distributed in the eastern Indian and western Pacific oceans, from India to Papua New Guinea, and from southern Japan to northern Australia. The L. splendens complex can be defined by the following combination of characters: body depth 42–60% of standard length; mouth protruding downward; slender, minute teeth uniserially on jaws; lower margin of orbit above the horizontal through the gape when mouth closed; breast almost completely scaled; lateral line complete, and a dark blotch on top of spinous dorsal fin. Diagnostic characters of the members are as follows: L. jonesi —anterior dorsolateral body surface with a semicircular naked area on nape, and a paler dark blotch on spinous dorsal fin; L. kupanensis —anterior dorsolateral body surface widely naked; L. rapsoni —cheek scaled; L. splendens —anterior dorsolateral body surface completely scaled and a jet black blotch on spinous dorsal fin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41595/1/10228_2005_Article_283.pd