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- W2214672889 abstract "AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA3097 A low extracellular pH has been associated with tumor progression and increased invasive capacity (Rofstad, et al. Cancer Res 2006(13): 6699-707). This condition induces an outward movement of lysosomes and release of proteases; however, the mechanisms regulating lysosome trafficking under these conditions remain largely undefined. To address the mechanisms regulating lysosome outward movement, we used the DU-145 prostate cancer cell line as a model. We found that a low extracellular pH of 6.4-6.8 rapidly induced a peripheral lysosome redistribution that was dependent upon intact microtubules, since nocodazole inhibited outward movement. Immunofluorescence microscopy indicated that lysosomes were the only endocytic organelles that underwent peripheral redistribution. In addition, the PI3-Kinase pathway and members of the Rho GTPase family also played roles since LY294002 (a specific PI3K inhibitor) and C3-Transferase (a Rho family inhibitor) inhibited lysosome movement. The sodium-proton exchanger NHE-1 plays a role in regulating intracellular pH, thus to determine the role of NHE-1 in regulating lysosome redistribution, we used two different inhibitors. Treatment with Troglitazone (Tro; also an anti-diabetic agent), not only inhibited lysosome redistribution, but also induced the clustering of lysosomes near the microtubule-organizing center. Ethyl-isopropyl-amiloride, another NHE-1 inhibitor, prevented the low extracellular pH induced outward movement of lysosomes, but did not cause a clustering of lysosomes. Furthermore, we have determined that in addition to microtubules, the MAP-Kinase pathway was involved in Troglitazone’s clustering effect since treatment with UO126 (a MAPK inhibitor) prevented lysosome clustering. In addition, DNA transfection experiments demonstrated that Rab7 and its downstream effector, RILP, also played a role in Tro induced lysosome clustering. Thus, a better understanding of the mechanisms by which Tro reverses lysosome redistribution will lead to novel therapeutic targets to reduce protease secretion, resulting in a decrease in tumor invasion." @default.
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- W2214672889 date "2007-05-01" @default.
- W2214672889 modified "2023-09-23" @default.
- W2214672889 title "Mechanisms regulating acidic extracellular pH induced lysosome trafficking in prostate cancer" @default.
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