inositol-1-4-5-trisphosphate and Neoplasm-Metastasis

Store-operated Ca(2+) entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca(2+) pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca(2+) levels within the endoplasmic reticulum (ER) Ca(2+) reservoir, and a number of a Ca(2+)-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1-7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients. SOCE was induced following pharmacological depletion of the ER Ca(2+) store, but not by InsP3-dependent Ca(2+) release. Metastatic RCC cells express Stim1-2, Orai1-3, and TRPC1-7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd(3+) and Pyr6, while it was inhibited by 100 µM Gd(3+), 2-APB, and carboxyamidotriazole (CAI). Neither Gd(3+) nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca(2+) signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors.

Topics: Aged; Calcium Channels; Calcium Signaling; Carcinoma, Renal Cell; Cell Proliferation; Endoplasmic Reticulum; Female; Humans; Inositol 1,4,5-Trisphosphate; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; ORAI1 Protein; Primary Cell Culture; Protein Kinase Inhibitors; Stromal Interaction Molecule 1; TRPC Cation Channels

One of the important functions of vascular endothelial cells is as a barrier between blood and vascular tissue. This led us to speculate that cancer cells affect endothelial cells during metastasis. In the present study, we investigated the influence of human fibrosarcoma cells (HT-1080) on human umbilical vein endothelial cells (HUVEC), particularly intracellular calcium ion levels ([Ca2+]i), which are known to be an important intracellular signal transduction factor. HUVEC were treated with a fluorescent marker, and the fluorescence intensity of [Ca2+]i was then measured by phase contrast microscopic imaging. Extracellular adenosine triphosphate (ATP) release was measured using the chemiluminescence of luciferin-luciferase and a photon counting imaging system. HT-1080 (5x10(4) cells per dish) was found to increase [Ca2+]i in HUVEC. This [Ca2+]i rise was significantly reduced by U-73122 (phospholipase C inhibitor, 1 microM) and thapsigargin (calcium pump inhibitor, 1 microM). Interestingly, the [Ca2+]i rise in HUVEC was also significantly reduced by pyridoxalphosphare-6-azophenyl-2', 4'-disulfonic acid, a P2Y receptor antagonist (100 microM) and apyrase, a nucleotidase inhibitor (2 U/ml). In addition, we observed ATP release from HT-1080. These results suggest that [Ca2+]i in HUVEC was increased through the phospholipase C-IP3 pathway via ATP release from cancer cells. We previously reported that extracellular ATP increased [Ca2+]i and enhanced macromolecular permeability via the P2Y receptor. In tumor metastasis, cancer cells may exploit these regulatory mechanisms in the endothelial cell layer.

Topics: Adenosine Triphosphate; Calcium; Cell Line; Cell Line, Tumor; Endothelial Cells; Fibrosarcoma; Humans; Inositol 1,4,5-Trisphosphate; Neoplasm Metastasis; Receptors, Purinergic P2; Type C Phospholipases; Umbilical Veins

To understand the role of NM23/NDPK in the transmembrane signal transduction proccess in tumor metastasis.. The NDPK activity, IP3 contents, the invasive potentials of the cells of mouse forestomach carcinoma(MFC) substrains with different metastatic potentials and the effect of LN and EGF were observed.. Both the NDPK activity and the contents of IP3 of the cells of the subclone with lower metastatic potential was higher than that with higher metastatic potential. Also, the cells with lower metastatic potential had lower invasive potential and higher responsibility to the challenge of EGF compared with that higher metastatic potential. However, no different effect of LN on the cells of those subclones was found.. NDPK might regulate the metastasis of FMC cells by impacting the G protein efficacy with the selection of exotic signal ligands.

Topics: Animals; Epidermal Growth Factor; Inositol 1,4,5-Trisphosphate; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Nucleoside-Diphosphate Kinase; Signal Transduction; Stomach Neoplasms; Tumor Cells, Cultured

To examine the IP3 amounts, invasive potentials, and response to LN and EGF of the substrains with high or low metastatic ability from two kinds of carcinoma cell lines (MFC and CNZ-2Z).. Radio-ligand binding assay and matrigel invasive assay.. The low metastatic substrains from the two lines had higher amounts of IP3 and stronger response to EGF than their responsive high ones, but high metastatic substrains from CNZ-2Z had stronger response to LN than the low ones while MFC substrains had not significant difference in response to LN.. There is internal difference in signal transduction between the high and low metastatic cancer cells, and it is significant to study the difference in detail.

Topics: Animals; Epidermal Growth Factor; Humans; Inositol 1,4,5-Trisphosphate; Laminin; Mice; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Signal Transduction; Stomach Neoplasms; Tumor Cells, Cultured