Malic enzyme 1 (ME1) regulates one of the main pathways that provide nicotinamide adenine dinucleotide phosphate (NADPH), which is essential for cancer cell growth through maintenance of redox balance and biosynthesis processes in the cytoplasm. In this study, we found that ME1 inhibition disrupted metabolism in cancer cells and inhibited cancer cell growth by inducing senescence or apoptosis. In glucose-restricted culture conditions, cancer cells increased ME1 expression, and tracer experiments with labelled glutamine revealed that the flux of ME1-derived pyruvate to citrate was enhanced. In addition, cancer cells showed higher sensitivity to ME1 depletion in glucose-restricted conditions compared to normal culture conditions. These results suggest that in a low-glucose environment, where glycolysis and the pentose phosphate pathway (PPP) is attenuated, cancer cells become dependent on ME1 for the supply of NADPH and pyruvate. Our data demonstrate that ME1 is a promising target for cancer treatment, and a strategy using ME1 inhibitors combined with inhibition of glycolysis, PPP or redox balance regulators may provide an effective therapeutic option.
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. 7,8,is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G 2 -M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC 50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC 50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700-9. Ó2011 AACR.
The CDK8/19 kinase module comprises a subcomplex that interacts with the Mediator complex and regulates gene expression through phosphorylation of transcription factors and Mediator subunits. Mediator complex subunits have been increasingly implicated in cancer and other diseases. Although high expression of CDK8/19 has been demonstrated in prostate cancer, its function has not been thoroughly examined. Here we report that CDK8/19 modulates the gene expression of cell cycle regulators and thereby maintains the proper G1/S transition in prostate cancer cells. We show that highly selective CDK8/19 inhibitors exerted anti-proliferative activity in prostate cancer cells both in vitro and in vivo. In CDK8/19 inhibitor-sensitive prostate cancer cells, the compounds reduced the population of G1 phase cells and elevated that of S phase cells through the modulation of G1/S transition regulators at the level of mRNA expression. Furthermore, the premature G1/S transition induced a DNA damage response that was followed by ATR-dependent and caspase-independent cell death. These findings suggest a novel role of CDK8/19 in transcription-mediated cell cycle control, albeit with possible contribution of other proteins inhibited by the compounds. Our data provide a rationale for further investigation of CDK8/19 inhibitors as a new therapeutic approach to prostate cancer.
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