Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells
ABSTRACT Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is the cornerstone of lung cancer chemotherapy. However, its efficacy is limited due to the development of drug resistance in cancer cells. This study was designed to uncover the mechanisms under CDDP resistance in lung cancer cells involving endoplasmic reticulum (ER) stress tolerance-induced and GRP78-dependant Akt activation. In this study we established ER stress-tolerant (ERST) human lung cancer lines H460et and A549et. We found that the ERST Lung cancer cells are resistant to CDDP treatment. We further showed that, compared to the parental cell lines, H460et and A549et show significantly increased GRP78 and phospho(p)-Akt levels. And phosphorylation of Akt, which can be regulated by GRP78, is essential to the ERST-associated CDDP resistance. Our findings identify a new mechanism of regulating Akt activity and a new mechanism through which CDDP resistance is formed in lung cancer cells.
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ABSTRACT: Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents and is widely used in the treatment of solid tumors. However, its side effects and acquired resistance gained during the course of treatment may limit its usage. It is generally considered to be a cytotoxic drug that kills cancer cells by damaging their DNA and inhibiting DNA synthesis to induce apoptosis via the mitochondrial death pathway or through plasma membrane disruption, triggering the Fas death receptor pathway. The endoplasmic reticulum (ER) is one of the most important protein-folding compartments within the cell and an intracellular Ca(2+) storage organelle. The ER contains a number of molecular chaperones, which may play an important role in determining cellular sensitivity to ER stress and apoptosis. The aim of this review was to summarize our current understanding regarding the mechanisms of ER stress response by which cisplatin induces cell death and the basis for cisplatin resistance. Various aspects were addressed, including the two-way regulation of ER stress, the involvement of ER stress in cisplatin-induced cell death and drug resistance and the drugs enhancing cisplatin-induced cell death by interfering with ER stress. An understanding of how ER stress signaling pathways regulate cisplatin-induced cell death may enable the development of more effective therapeutic strategies for the treatment of cancer.Molecular and Clinical Oncology 01/2014; 2(1):3-7. DOI:10.3892/mco.2013.202
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ABSTRACT: Abstract In this study, we show that exposure of human lung cancer A549 cells to cisplatin (cis-diamminedichloroplatinum, CDDP) promotes production of nitric oxide (NO) through generation of reactive oxygen species (ROS) and resultant up-regulation of inducible NO synthase (iNOS). The incubation of the cells with a NO donor diethylenetriamine NONOate not only reduced the CDDP-induced cell death and apoptotic alterations (induction of CCAAT-enhancer-binding protein homologous protein and caspase-3 activation), but also elevated proteolytic activity of 26S proteasome, suggesting that the activation of proteasome function contributes to the reduction of CDDP sensitivity by NO. Monitoring of expression levels of six aldo-keto reductases (AKRs: 1A1, 1B1, 1B10, 1C1, 1C2 and 1C3) during the treatment with the NO donor and subsequent CDDP sensitivity test using the specific inhibitors also proposed that up-regulation of AKR1B10 by NO is a key process for acquiring the CDDP resistance in A549 cells. Treatment with CDDP and NO increased amounts of nitrotyrosine-protein adducts, indicative of peroxynitrite formation, and promoted the induction of AKR1B10, inferring a relationship between peroxynitrite formation and the enzyme up-regulation in the cells. The treatment with CDDP or a ROS-related lipid aldehyde 4-hydroxy-2-nonenal facilitated the iNOS up-regulation, which was restored by increasing the AKR1B10 expression. In contrast, the facilitation of NO production by CDDP treatment was hardly observed in AKR1B10-overexpressing A549 cells and established CDDP-resistant cancer cells (A549, LoVo and PC3). Collectively, these results suggest the NO functions as a key regulator controlling AKR1B10 expression and 26S proteasome function leading to gain of the CDDP resistance.Free Radical Research 08/2014; 48(11):1-32. DOI:10.3109/10715762.2014.957694 · 2.99 Impact Factor
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ABSTRACT: Endometrial cancer (EC) is a common gynecologic malignancy often diagnosed at early stage. In spite of a huge advance in our understanding of EC biology, therapeutic modalities do not have significantly changed over the past 40 years. A restricted number of genes have been reported to be mutated in EC, mediating cell proliferation and invasiveness. However, besides these alterations, few other groups and ourselves recently identified the activation of the unfolded protein response (UPR) and GRP78 increase following endoplasmic reticulum (ER) stress as mechanisms favoring growth and invasion of EC cells. Here, a concise update on currently available data in the field is presented, analyzing the crosstalk between the UPR and the main signaling pathways regulating EC cell proliferation and survival. It is evident that this is a rapidly expanding and promising issue. However, more data are very likely to yield a better understanding on the mechanisms through which EC cells can survive the low oxygen and glucose tumor microenvironment. In this perspective, the UPR and, particularly, GRP78 might constitute a novel target for the treatment of EC in combination with traditional adjuvant therapy.12/2014; 1:55. DOI:10.3389/fmed.2014.00055