Acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) phosphorylates and regulates the function of many cellular proteins involved in processes such as metabolism, apoptosis and proliferation. However, the precise mechanisms by which Akt promotes cell survival and inhibits apoptosis have been characterized in part only. TR3, an orphan receptor, functions as a transcription factor that can both positively or negatively regulate gene expression. We have reported previously that the translocation of TR3 from the nucleus to the mitochondria can elicit a proapoptotic effect in gastric cancer cells. In our present study, we demonstrate that Akt phosphorylates cytoplasmic TR3 through its physical interaction with the N-terminus of TR3. When coexpressed with Akt, TR3 mitochondrial targeting was blocked and this protein adopted a diffuse expression pattern in the cytoplasm. Moreover, Akt displayed an ability to disrupt the interaction of TR3 with Bcl-2, which is thought to be a critical requirement for mitochondrial TR3 to elicit apoptosis. Consistently, insulin was also found to induce the phosphorylation of TR3 and abolish 12-O-tetradecanoylphorbol-13-acetate-induced mitochondrial localization, which was dependent upon the activation of the phophatidylinositol-3-OH-kinase-Akt signaling pathway. Taken together, our current data demonstrate a unique role for Akt in inhibiting TR3 functions that are not related to transcriptional activity but that correlate with the regulation of its mitochondrial association. This may represent a novel signal pathway by which Akt exerts its antiapoptotic effects in gastric cancer cells, i.e. by regulating the phosphorylation and redistribution of orphan receptors.

Upregulation of glycolysis and the pentose phosphate pathway (PPP) is a major characteristic of the metabolic reprogramming of cancer and provides cancer cells with energy and vital metabolites to support their rapid proliferation. Targeting glycolysis and the PPP has emerged as a promising antitumor therapeutic strategy. Marine natural products are attractive sources for anticancer therapeutics, as evidenced by the antitumor drug Yondelis. Mycoepoxydiene (MED) is a natural product isolated from a marine fungus that has shown promising inhibitory efficacy against HeLa cells in vitro. We used a proteomic approach with two-dimensional gel electrophoresis (2-DE) coupled with mass spectrometry to explore the cellular targets of MED and to unravel the molecular mechanisms underlying the antitumor activity of MED in HeLa cells. Our proteomic data showed that triosephosphate isomerase (TPI) and 6-phosphogluconolactonase (PGLS), which participate in glycolysis and the PPP, respectively, were significantly downregulated by MED treatment. Functional studies revealed that the expression levels of several other enzymes involved in glycolysis and the PPP, including hexokinase 2 (HK2), phosphofructokinase 1 (PFKM), aldolase A (ALDOA), enolase 1 (ENO1), lactate dehydrogenase A (LDHA), and glucose-6-phosphate dehydrogenase (G6PD), were also reduced in a dose-dependent manner. Moreover, the LDHA and G6PD enzymatic activities in HeLa cells were inhibited by MED, and overexpression of these downregulated enzymes rescued HeLa cells from the growth inhibition induced by MED. Our data suggest that MED suppresses HeLa cell growth by inhibiting glycolysis and the PPP, which provides a mechanistic basis for the development of new therapeutics against cervical cancer.

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Background Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Dysfunction of E74-like ETS transcription factor 4 (ELF4) leads to inflammation. This research intended to look into the function and mechanisms of ELF4 in I/R and oxygen–glucose deprivation/reperfusion (OGD/R) model. Results In I/R and OGD/R model, ELF4 expression was downregulated. ELF4 knockout aggravated I/R-induced kidney injury, oxidative stress (OS), endoplasmic reticulum stress (ERS), apoptosis, inflammation, and pyroptosis in mice. In HK-2 cells treated with OGD/R, suppression of ELF4 expression inhibited cell proliferation and promoted cell apoptosis, OS, ERS, inflammation, and pyroptosis. Moreover, ELF4 overexpression led to the opposite results. Conclusion ELF4 deficiency aggravated I/R induced AKI, which was involved in apoptosis, OS, ERS, inflammation, and pyroptosis. Targeting ELF4 may be a promising new therapeutic strategy for preventing inflammation after IR-AKI.