Abstract
BackgroundIn contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1), and its presence in tumor patients is associated with poor prognosis. Thus, necrosis has important clinical implications in tumor development; however, its molecular mechanism remains poorly understood.ResultsIn the present study, we show that Distal-less 2 (Dlx-2), a homeobox gene of the Dlx family that is involved in embryonic development, is induced in cancer cell lines dependently of reactive oxygen species (ROS) in response to glucose deprivation (GD), one of the metabolic stresses occurring in solid tumors. Increased Dlx-2 expression was also detected in the inner regions, which experience metabolic stress, of human tumors and of a multicellular tumor spheroid, an in vitro model of solid tumors. Dlx-2 short hairpin RNA (shRNA) inhibited metabolic stress-induced increase in propidium iodide-positive cell population and HMGB1 and lactate dehydrogenase (LDH) release, indicating the important role(s) of Dlx-2 in metabolic stress-induced necrosis. Dlx-2 shRNA appeared to exert its anti-necrotic effects by preventing metabolic stress-induced increases in mitochondrial ROS, which are responsible for triggering necrosis.ConclusionsThese results suggest that Dlx-2 may be involved in tumor progression via the regulation of metabolic stress-induced necrosis.
Highlights
In contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1), and its presence in tumor patients is associated with poor prognosis
We showed that phorbol-12-myristate13-acetate (PMA), a protein kinase C (PKC) activator, prevented glucose deprivation (GD)-induced necrosis in A549 cells, and switched the cell death mode to apoptosis by inhibiting reactive oxygen species (ROS) production by regulating manganese superoxide dismutase (MnSOD) and copperzinc SOD [32]
One of the GD-inducible genes was Dlx-2, a homeobox gene of the Dlx family (Figure 1C); the Dlx-2 level was increased 9.04-fold during necrosis, whereas its level was not changed during apoptosis
Summary
In contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1), and its presence in tumor patients is associated with poor prognosis. Under circumstances of hypoxia and nutrient deprivation, tumor cells either survive by overcoming the cytotoxic effects of such metabolic stresses via the activation of certain signal transduction pathways and gene regulatory mechanisms, or undergo cell death, especially in the innermost regions [1,2,3,4]. In contrast to programmed cell death, apoptosis, and autophagic cell death, the molecular mechanism underlying metabolic stress-induced necrosis in tumors is less investigated because it is generally considered as an accidental and genetically unprogrammed form of cell death
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