Proper control of Ca(2+) signaling is mandatory for effective cell migration, which is critical for embryonic development, wound healing, and cancer metastasis. However, how Ca(2+) coordinates structural components and signaling molecules for proper cell motility had remained elusive. With the advance of fluorescent live-cell Ca(2+) imaging in recent years, we gradually understand how Ca(2+) is regulated spatially and temporally in migrating cells, driving polarization, protrusion, retraction, and adhesion at the right place and right time. Here we give an overview about how cells create local Ca(2+) pulses near the leading edge, maintain cytosolic Ca(2+) gradient from back to front, and restore Ca(2+) depletion for persistent cell motility. Differential roles of Ca(2+) in regulating various effectors and the interaction of roles of Ca(2+) signaling with other pathways during migration are also discussed. Such information might suggest a new direction to control cancer metastasis by manipulating Ca(2+) and its associating signaling molecules in a judicious manner.

/pdf/ca2-signaling-in-cytoskeletal-reorganization-cell-migration-2aom050m7d.pdf

Ca2+ Signaling in Cytoskeletal Reorganization, Cell Migration, and Cancer Metastasis

Objective Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.

/pdf/thapsigargin-induces-apoptosis-in-adrenocortical-carcinoma-2kcoew30w2.pdf

Thapsigargin induces apoptosis in adrenocortical carcinoma by activating endoplasmic reticulum stress and the JNK signaling pathway: an in vitro and in vivo study.

Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer’s disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53-responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro-apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway.

/pdf/cofilin-mediated-neuronal-apoptosis-via-p53-translocation-1a5e4tk1pg.pdf

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

Predictive factors for treatment response using dual-energy computed tomography in patients with advanced lung adenocarcinoma.

Blood brain barrier (BBB) is formed by the brain microvascular endothelial cells (BMVECs) lining the wall of brain capillaries. Its integrity is regulated by multiple mechanisms, including up/downregulation of tight junction proteins or adhesion molecules, altered Ca2+ homeostasis, remodeling of cytoskeleton, that are confined at the level of BMVECs. Beside the contribution of BMVECs to BBB permeability changes, other cells, such as pericytes, astrocytes, microglia, leukocytes or neurons, etc. are also exerting direct or indirect modulatory effects on BBB. Alterations in BBB integrity play a key role in multiple brain pathologies, including neurological (e.g. epilepsy) and neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis etc.). In this review, the principal Ca2+ signaling pathways in brain microvascular endothelial cells are discussed and their contribution to BBB integrity is emphasized. Improving the knowledge of Ca2+ homeostasis alterations in BMVECa is fundamental to identify new possible drug targets that diminish/prevent BBB permeabilization in neurological and neurodegenerative disorders.

Ca2+ homeostasis in brain microvascular endothelial cells.

The study aimed to investigate the relationship between the expressions of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), microvessel density (MVD) and the appearances on enhanced CT scan in lung cancer patients. Findings on dynamic CT scan were evaluated respectively in 35 patients without lung cancer (control) and 25 lung cancer patients receiving chemotherapy or radiotherapy followed by complete resection. Immunohistochemistry was used to detect the expressions of COX-2, VEGF and MVD and the relationships between CT enhancement value, histological types, clinic stages, lymph node metastasis, differentiation grades and the expressions of COX-2, VEGF and MVD were evaluated. The expressions of COX-2, VEGF and MVD (t = 11.615, 14.187, 10.524, respectively; P<0.05) and the CT enhancement value (q = 21.59, 67.81, respectively; P<0.01) in the lung cancer group were significantly higher than those in the control group. In addition, the expressions of COX-2, VEGF and MVD were related to the CT enhancement value, histological types, clinic stages and lymph node metastasis, but have no relevance with the differentiation grades among lung cancer patients. Dynamic CT enhancement scans can reflect the vascularity of lung cancer.

	 

	Key words: Lung cancer, immunohistochemistry, cyclooxygenase-2, vascular endothelial growth factor, microvessel density, CT enhancement value.

/pdf/role-of-time-density-curve-of-ct-enhancement-in-combination-1ubggg8itb.pdf

Role of time-density curve of ct enhancement in combination with pathological examination in the diagnose of lung cancer

The objective of this study was performed to investigate the effects of thapsigargin on apoptosis, actin cytoskeletal dynamics, and actin cytoskeletal proteins in human lung adenocarcinoma cell. Thapsigargin is a specific irreversible inhibitor of ER calcium-ATPase, which may promote ER stress by depletion of lumenal calcium stores and show potential to induce cell death. The effects of thapsigargin on the apoptosis in A549 cells were assayed by Hoechst staining. Moreover, the F-actin staining by Rhodamine-phalloidin and RhoA antibody for cytoskeleton organizations were applied to A549 cells. To confirm the impairment of cytoskeletal dynamics treated with thapsigargin, western blots were applied to analyze the protein levels of p-Cofilin-1 (Ser3), Cofilin-1, and pPaxillin (Tyr118), as well as RhoA and pS6 (S240/244). Results suggest that thapsigargin may induce cell death in A549 cells with a time- and dose-dependent manner. The F-actin fibers and RhoA signals are also reduced with a time- and dose-dependent manner by thapsigargin treatment. The phosphorylation forms of Cofilin-1 and paxillin are attenuated by 1 μM thapsigargin treatment for 24 h. These alternations may be caused by the inhibition of of mTORC1 activities (indicated by pS6 (Ser240/244)) and RhoA pathways after thapsigargin treatment. The present findings highlight important roles of calcium entry in cytoskeleton organization and apoptosis in human lung adenocarcinoma cells and will help to set a stage to the clinical treatment of cancer cell metastasis.

https://downloads.hindawi.com/journals/tswj/2014/619050.pdf

Thapsigargin induces apoptosis by impairing cytoskeleton dynamics in human lung adenocarcinoma cells.

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Role of time-density curve of ct enhancement in combination with pathological examination in the diagnose of lung cancer

Thapsigargin induces apoptosis by impairing cytoskeleton dynamics in human lung adenocarcinoma cells.