The endoplasmic reticulum (ER) is involved in many cellular functions, including protein folding and Ca(2+) homeostasis. The ability of cells to respond to the ER stress is critical for cell survival, and disruption in such regulation can lead to apoptosis. ER stress is accompanied by alterations in Ca(2+) homeostasis, and the ER Ca(2+) store depletion by itself can induce ER stress and apoptosis. Despite that, the ER Ca(2+) leak channels activated in response to the ER stress remain poorly characterized. Here we demonstrate that ER Ca(2+) depletion during the ER stress occurs via translocon, the ER protein complex involved in translation. Numerous ER stress inducers stimulate the ER Ca(2+) leak that can be prevented by translocon inhibitor, anisomycin. Expression of GRP78, an ER stress marker, increased following treatment with puromycin (a translocon opener) and was suppressed by anisomycin, confirming a primary role of translocon in ER stress induction. Inhibition of ER store depletion by anisomycin significantly reduces apoptosis stimulated by the ER stress inducers. We suggest that translocon opening is physiologically modulated by GRP78, particularly during the ER stress. The ability to modulate the ER Ca(2+) permeability and subsequent ER stress can lead to development of a novel therapeutic approach.
Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the K Ca 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, K Ca 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased K Ca 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on K Ca 3.1 activity. Mechanistically, elevated K Ca 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca 21 influx. K Ca 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased K Ca 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients.Lung cancer is a leading cause of cancer-related death. 1 The 5-year survival rate of patients with non-small-cell lung cancer (NSCLC), which accounts for 80% of lung cancers, may be as low as $10%. 2-4 Unfortunately, many patients develop local or distant metastasis relapse even after complete resection. Thus, high aggressiveness is an intrinsic feature of many NSCLC tumors. Adjuvant and palliative chemotherapy are of limited benefit in NSCLC, and novel therapeutic targets are needed.Individual NSCLC cancers harbor multiple mutations in protein-coding genes, most of which cannot be targeted therapeutically. 5 In contrast, epigenetic changes might be targetable. Effector mechanisms, e.g., for metastatic spread, could be promising therapeutic targets. Metastasis development originates from subpopulations of tumor cells that acquire additional features for increased aggressiveness. These features depend on changes in gene expression, including that of ion channels, 6-8 presumably often by epigenetic mechanisms rather than metastasis-specific mutations. 9-11 Altered DNA methylation of specific loci as a stable epigenetic mark is a likely culprit in many instances. DNA hypermethylation and gene silencing occur in CpG islands and promoters of tumor suppressors. 9 DNA hypomethylation is thought to occur mainly in intergenic regions, with effects mainly on genome stability. 9 However, the potential pathophysiological and clinical relevance of DNA hypomethylation of specific
Breast cancer (BC) has a poor prognosis due to its strong metastatic ability. Accumulating data present ether à go-go (hEag1) K(+) channels as relevant player in controlling cell cycle and proliferation of non-invasive BC cells. However, the role of hEag1 in invasive BC cells migration is still unknown. In this study, we studied both the functional expression and the involvement in cell migration of hEag1 in the highly metastatic MDA-MB-231 human BC cells. We showed that hEag1 mRNA and proteins were expressed in human invasive ductal carcinoma tissues and BC cell lines. Functional activity of hEag1 channels in MDA-MB-231 cells was confirmed using astemizole, a hEag1 blocker, or siRNA. Blocking or silencing hEag1 depolarized the membrane potential and reduced both Ca(2+) entry and MDA-MB-231 cell migration without affecting cell proliferation. Recent studies have reported that Ca(2+) entry through Orai1 channels is required for MDA-MB-231 cell migration. Down-regulation of hEag1 or Orai1 reduced Ca(2+) influx and cell migration with similar efficiency. Interestingly, no additive effects on Ca(2+) influx or cell migration were observed in cells co-transfected with sihEag1 and siOrai1. Finally, both Orai1 and hEag1 are expressed in invasive breast adenocarcinoma tissues and invaded metastatic lymph node samples (LNM(+)). In conclusion, this study is the first to demonstrate that hEag1 channels are involved in the serum-induced migration of BC cells by controlling the Ca(2+) entry through Orai1 channels. hEag1 may therefore represent a potential target for the suppression of BC cell migration, and thus prevention of metastasis development.
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