Sequestration of sorcin by aberrant forms of tau results in the defective calcium homeostasis

Neurofi brillary tangles (NFTs) of microtubule-associated protein tau are a pathological hallmark of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been known to be involved in the pathogenesis of AD. However, the exact role of ER stress in tau pathology has not yet been clearly elucidated. In present study, the possible relationship between tau pathology and ER stress was examined in terms of sorcin, which is a calcium binding protein and plays an important role in calcium homeostasis. Our previous yeast two hybrid study showed that sorcin is a novel tau interacting protein. Caspase-3-cleaved tau (T4C3) showed significantly increased tau-sorcin interaction compared to wild type tau (T4). Thapsigargin-induced ER stress and co-expression of constitutively active GSK3β (GSK3β-S9A) also exhibited significantly increased tau-sorcin interactions. T4C3-expressing cells showed potentiated thapsigargin-induced apoptosis and disruption of intracellular calcium homeostasis compared to T4-expressing cells. Overexpression of sorcin signifi cantly attenuated thapsigargin-induced apoptosis and disruption of calcium homeostasis. In contrary, siRNA-mediated knock-down of sorcin showed significantly increased thapsigargin-induced apoptosis and disruption of calcium homeostasis. These data strongly suggest that sequestration of sorcin by aberrant forms of tau compromises the function of sorcin, such as calcium homeostasis and cellular resistance by ER stress, which may consequently result in the contribution to the progression of AD.

The effect and mechanism of Sorcin silencing on drug resistance of human ovarian cancer SKOV3/CDDP cell lines / 中国癌症杂志

Background and purpose:Multi-drug resistance is a major reason for the chemotherapy failure of human ovarian cancer. Sorcin was found overexpression in drug resistance tumors and it may be the target of multi-drug resistance reversal. The present article was aimed to study the effect and mechanism of Sorcin silencing on drug resistance of human ovarian cancer SKOV3/CDDP cell lines. Methods:The stable Sorcin silencing SKOV3/CDDP cell lines were established. MTS assay, flow cytometry was used to analyze the intra-cellular Rh-123 content, cells apoptosis and cycle. Real-time, Western blot and report gene assay were used to analyze the expression changes of genes, including MDR1, MPR1, Survivin, Bcl-2, p-Akt and NF-κB. Results:Sorcin inhibition enhanced the drug sensitivity of SKOV3/CDDP cells, increased the intra-cellular Rh-123 content and cell apoptosis, and arrested cell cycle in G2/M. The protein levels of MDR1, MPR1, Survivin, Bcl-2, p-Akt were down-regulated, the mRNA levels of MDR1 of Sh-Sorcin-1 and Sh-Corcin-2 group were decreased to 42.3%and 26.5%of untransfected control, MRP1 were decreased to 33.2%and 18.9%of untransfected control, Survivin were decreased to 36.2%and 29.6%of untransfected control, Bcl-2 were decreased to 54.6%and 46.7%of untransfected control, transcriptional activity of NF-κB were decreased to 56.3%and 38.4%of untransfected control respectively inSKOV3/CDDP cell lines after Sorcin silence. Conclusion: Sorcin silencing could reverse SKOV3/CDDP drug resistance and enhance drug sensitivity, which involves the decreased phosphorylation level of Akt and transcriptional activity of NF-κB.