Thiazolidinediones induce Rab7-RILP-MAPK-dependent juxtanuclear lysosome aggregation and reduce tumor cell invasion.
Acidic extracellular pH (pHe) has been shown to stimulate peripheral lysosome trafficking, resulting in cathepsin B secretion and tumor invasion. In addition, inhibitors of sodium-proton exchangers (NHE) such as EIPA, cariporide and s3226, as well as the non-specific NHE inhibitor, troglitazone (Tro), blocked these changes. In this paper, we report a differential ability of the thiazolidinedione (TZD) family of compounds to induce a time-dependent retrograde aggregation of lysosomes over the microtubule-organizing center (MTOC) in tumor cells exposed to acidic pHe. This trafficking event depended on microtubules and the MAP-Kinase pathway, but was independent of Rho GTPase activity. Expression of shRNA implicated Rab7 in this process, and subcellular fractionation revealed that levels of Rab7, RILP and Erk1/2 were increased on lysosomes purified from cells treated with Tro. In addition, DN-RILP overexpression studies indicated that this Rab7 effector also played a role in TZD-induced retrograde trafficking. Tro was able to prevent acidic pHe-induced cell invasion. Finally, DU145 prostate tumor cells stably over-expressing WT-RILP, a condition where lysosomes aggregate to the MTOC in the absence of Tro, did not invade in response to acidic pHe, suggesting that the regulation of lysosome trafficking is an inherently important aspect of tumor cell invasion.
Steffan
Joshua J
JJ
Department of Microbiology and Immunology and The Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Cardelli
James A
JA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; C423317:RILP protein, human; D045162:Thiazolidinediones; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D020691:rab GTP-Binding Proteins