Expression of PTRF in PC-3 Cells Modulates Cholesterol Dynamics and the Actin Cytoskeleton Impacting Secretion Pathways

Expression of caveolin-1 is up-regulated in prostate cancer metastasis and is associated with aggressive recurrence of the disease. Intriguingly, caveolin-1 is also secreted from prostate cancer cell lines and has been identified in secreted prostasomes. Caveolin-1 is the major structural component of the plasma membrane invaginations called caveolae. Co-expression of the coat protein Polymerase I and transcript release factor (PTRF) is required for caveolae formation. We recently found that expression of caveolin-1 in the aggressive prostate cancer cell line PC-3 is not accompanied by PTRF, leading to noncaveolar caveolin-1 lipid rafts. Moreover, ectopic expression of PTRF in PC-3 cells sequesters caveolin-1 into caveolae. Here we quantitatively analyzed the effect of PTRF expression on the PC-3 proteome using stable isotope labeling by amino acids in culture and subcellular proteomics. We show that PTRF reduced the secretion of a subset of proteins including secreted proteases, cytokines, and growth regulatory proteins, partly via a reduction in prostasome secretion. To determine the cellular mechanism accounting for the observed reduction in secreted proteins we analyzed total membrane and the detergent-resistant membrane fractions. Our data show that PTRF expression selectively impaired the recruitment of actin cytoskeletal proteins to the detergent-resistant membrane, which correlated with altered cholesterol distribution in PC-3 cells expressing PTRF. Consistent with this, modulating cellular cholesterol altered the actin cytoskeleton and protein secretion in PC-3 cells. Intriguingly, several proteins that function in ER to Golgi trafficking were reduced by PTRF expression. Taken together, these results suggest that the noncaveolar caveolin-1 found in prostate cancer cells generates a lipid raft microenvironment that accentuates secretion pathways, possibly at the step of ER sorting/exit. Importantly, these effects could be modulated by PTRF expression. Expression of caveolin-1 is up-regulated in prostate cancer metastasis and is associated with aggressive recurrence of the disease. Intriguingly, caveolin-1 is also secreted from prostate cancer cell lines and has been identified in secreted prostasomes. Caveolin-1 is the major structural component of the plasma membrane invaginations called caveolae. Co-expression of the coat protein Polymerase I and transcript release factor (PTRF) is required for caveolae formation. We recently found that expression of caveolin-1 in the aggressive prostate cancer cell line PC-3 is not accompanied by PTRF, leading to noncaveolar caveolin-1 lipid rafts. Moreover, ectopic expression of PTRF in PC-3 cells sequesters caveolin-1 into caveolae. Here we quantitatively analyzed the effect of PTRF expression on the PC-3 proteome using stable isotope labeling by amino acids in culture and subcellular proteomics. We show that PTRF reduced the secretion of a subset of proteins including secreted proteases, cytokines, and growth regulatory proteins, partly via a reduction in prostasome secretion. To determine the cellular mechanism accounting for the observed reduction in secreted proteins we analyzed total membrane and the detergent-resistant membrane fractions. Our data show that PTRF expression selectively impaired the recruitment of actin cytoskeletal proteins to the detergent-resistant membrane, which correlated with altered cholesterol distribution in PC-3 cells expressing PTRF. Consistent with this, modulating cellular cholesterol altered the actin cytoskeleton and protein secretion in PC-3 cells. Intriguingly, several proteins that function in ER to Golgi trafficking were reduced by PTRF expression. Taken together, these results suggest that the noncaveolar caveolin-1 found in prostate cancer cells generates a lipid raft microenvironment that accentuates secretion pathways, possibly at the step of ER sorting/exit. Importantly, these effects could be modulated by PTRF expression. Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer related deaths in developed countries. Although localized prostate cancer is treatable, metastatic recurrence, together with development of androgen-independence, leads to advanced prostate cancer, which currently has a low survival rate. Caveolin-1, a cholesterol-binding integral membrane protein, has been shown to be up-regulated in prostate cancer metastasis and is associated with androgen-independence and aggressive recurrence of the disease (1Bennett N. Hooper J.D. Lee C.S. Gobe G.C. Androgen receptor and caveolin-1 in prostate cancer.IUBMB Life. 2009; 61: 961-970Crossref PubMed Scopus (24) Google Scholar). A prostate cancer mouse model showed that genetic ablation of caveolin-1 delays the onset of advanced prostate cancer (2Williams T.M. Hassan G.S. Li J. Cohen A.W. Medina F. Frank P.G. Pestell R.G. Di Vizio D. Loda M. Lisanti M.P. Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer: genetic ablation of Cav-1 delays advanced prostate tumor development in tramp mice.J. Biol. Chem. 2005; 280: 25134-25145Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), underscoring its importance in prostate cancer progression. Hence understanding caveolin-1 action in prostate cancer progression is crucial for the design of novel intervention strategies to manage this devastating disease. Caveolin-1 is a major structural component of caveolae, specialized lipid raft microdomains of the plasma membrane characterized by their flask shaped invaginations (3Parton R.G. Simons K. The multiple faces of caveolae.Nat. Rev. Mol. Cell Biol. 2007; 8: 185-194Crossref PubMed Scopus (1155) Google Scholar). Lipid rafts and caveolae are thought to participate in a variety of cellular processes including lipid regulation, endocytosis, cell adhesion, and signal transduction (4Parton R.G. Richards A.A. Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms.Traffic. 2003; 4: 724-738Crossref PubMed Scopus (494) Google Scholar). However, a clear delineation between lipid rafts and caveolae function remains to be made. Recently, it was revealed that the protein Polymerase I and transcript release factor (PTRF) 1The abbreviations used are:PTRFpolymerase I and transcript release factorDRMsdetergent-resistant membranesLC-MS/MSliquid chromatography-tandem mass spectrometrySILACstable isotope labeling by amino acids in cell cultureMβCDmethyl-β-cyclodextrinIL-6Interleukin-6KLK-6Kallikrein 6PBSphosphate-buffered saline. 1The abbreviations used are:PTRFpolymerase I and transcript release factorDRMsdetergent-resistant membranesLC-MS/MSliquid chromatography-tandem mass spectrometrySILACstable isotope labeling by amino acids in cell cultureMβCDmethyl-β-cyclodextrinIL-6Interleukin-6KLK-6Kallikrein 6PBSphosphate-buffered saline., also known as cavin-1, is an essential cofactor required for stabilization of caveolae at the plasma membrane (5Hill M.M. Bastiani M. Luetterforst R. Kirkham M. Kirkham A. Nixon S.J. Walser P. Abankwa D. Oorschot V.M. Martin S. Hancock J.F. Parton R.G. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell. 2008; 132: 113-124Abstract Full Text Full Text PDF PubMed Scopus (526) Google D. M. D. K. of of caveolae, and 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). The of PTRF results in the of caveolae, as as a in caveolin-1 (5Hill M.M. Bastiani M. Luetterforst R. Kirkham M. Kirkham A. Nixon S.J. Walser P. Abankwa D. Oorschot V.M. Martin S. Hancock J.F. Parton R.G. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell. 2008; 132: 113-124Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar). results a crucial for PTRF in caveolae and these new the of PTRF in to its function in caveolae is to be in prostate cancer in caveolae, and and transcript release factor (PTRF) expression in prostate cancer PubMed Scopus Google Scholar). I and transcript release factor detergent-resistant chromatography-tandem mass stable isotope labeling by amino acids in cell culture saline. I and transcript release factor detergent-resistant chromatography-tandem mass stable isotope labeling by amino acids in cell culture saline. Intriguingly, caveolin-1 is a membrane protein, aggressive prostate cancer cell lines been shown to caveolin-1 S. Li A. M. J.D. caveolin-1 cell growth and to metastasis in prostate 61: Google Scholar). secreted caveolin-1 cell growth and in tumor S. Li A. M. J.D. caveolin-1 cell growth and to metastasis in prostate 61: Google A.A. M. K. J. D. caveolin-1 has in prostate 2008; PubMed Scopus Google Scholar). caveolin-1 has been in prostate cancer and has been to be a for disease recurrence S. Li A. M. J.D. caveolin-1 cell growth and to metastasis in prostate 61: Google R. J.D. A. T.M. of an for a novel for prostate 2003; Google Scholar). to prostate cells also proteins via to as prostasomes. is thought that are in a to that via that cytoplasmic proteins S. and Rev. PubMed Scopus Google Scholar). Prostate cells into the prostate related to recently it has that prostate cancer cell lines also and it is thought to the tumor J. A. R. T.M. secretion of cytoplasmic prostate cancer 2009; 8: Full Text Full Text PDF PubMed Scopus Google A. Caveolin-1 and are on secreted by the prostate cancer PC-3 cell Cell PubMed Scopus Google A. K. prostasome release from in PC-3 prostate cancer J. Biol. 2007; PubMed Scopus Google Scholar). secretion is modulated by cholesterol and caveolin-1 has been identified as a component of in the prostate PC-3 cell line A. Caveolin-1 and are on secreted by the prostate cancer PC-3 cell Cell PubMed Scopus Google Scholar). data to the of caveolin-1 and PTRF in secretion of prostate cancer cells. We shown that PC-3 cells caveolin-1 PTRF, and that ectopic expression of PTRF in PC-3 cells results in caveolae formation (5Hill M.M. Bastiani M. Luetterforst R. Kirkham M. Kirkham A. Nixon S.J. Walser P. Abankwa D. Oorschot V.M. Martin S. Hancock J.F. Parton R.G. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell. 2008; 132: 113-124Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar). PTRF expression in PC-3 cells in reduced partly of of secreted C.S. M.M. Bastiani M. Parton R.G. expression the of prostate cancer of J. Cell Biol. PubMed Scopus Google Scholar). that caveolin-1 and caveolae participate in a of cellular we subcellular using PC-3 cell which (5Hill M.M. Bastiani M. Luetterforst R. Kirkham M. Kirkham A. Nixon S.J. Walser P. Abankwa D. Oorschot V.M. Martin S. Hancock J.F. Parton R.G. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell. 2008; 132: 113-124Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar), in to a of by PTRF expression. of the subcellular to a for PTRF in modulating cholesterol and of the actin the trafficking of multiple secretion Importantly, PTRF reduced the secretion of a subset of proteins including secreted proteases, cytokines, and growth Our the for PTRF as a that could a of secreted a The were from the and cell culture were from was from and and and were from and were from was from was from caveolin-1 and were from A was from PTRF were by with a to the amino acids of mouse PTRF, and from M. M.M. M.P. Nixon S.J. Abankwa D. Luetterforst R. M. J. Walser Hancock J.F. Parton R.G. and Cell Biol. 2009; PubMed Scopus Google Scholar). has been (5Hill M.M. Bastiani M. Luetterforst R. Kirkham M. Kirkham A. Nixon S.J. Walser P. Abankwa D. Oorschot V.M. Martin S. Hancock J.F. Parton R.G. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell. 2008; 132: 113-124Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar). PC-3 and PC-3 stable cells were and in cell lines were in and PC-3 cells were in and with and with the amino for the and and for and Cell were in the labeling to as by chromatography-tandem cells were using to the to of PC-3 cells were used for total membrane, detergent-resistant membrane secreted proteome and prostasome PC-3 cells to to were with and for in cell was by at for at cell culture was an and protein was using protein of from the cell lines were for of of from to cell not at of the at were with and at were in The was from cells as D. N. A. Martin S. A. D. Parton R.G. M.M. Hancock J.F. and plasma membrane and signal Biol. Chem. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). were by cells in and on for protein were using and protein from were were to by of an of by of and The were for at and the between and The was with and by at for were at were with in and for at of was reduced with with and of was to the were also by into using and were analyzed using a and were by with from to with the were in the of and at was were analyzed in with and data are at and were using and amino acids and were used as a as and was as to for and for and required a protein and were from and was using the to a protein, and were using the were by the of by a M. M. D. 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PubMed Scopus Google Scholar). cell and between cellular and secreted proteases, we the data for proteins with a in cancer and cell using revealed that PTRF expression most the secretion of proteins in cell and cytoskeleton PTRF modulated in the prostasome the prostasome is a of the for the is that PTRF expression the secretion of To this we analyzed the proteins common to the and prostasome The that proteins were identified in that a of total secreted the subset of proteins by PTRF were common to the and that the reduction in secreted proteins PTRF expression could be by a reduction in of the proteins reduced in the and prostasome by PTRF expression identified a of proteins with to cancer and in including proteins, secreted proteases, and We proteins that been in prostate cancer J. M. M. M. as a factor in with prostate Google Simons a of prostate cancer Full Text PDF PubMed Scopus Google J. of tumor for prostate cancer via of cell Chem. 2007; PubMed Scopus Google for by and To the stable cell line we of PC-3 cells for these from PC-3 cells with were with and that expression of PTRF reduced secreted and cell of and cells showed in expression that PTRF expression not total cellular of and their of proteins that were reduced in the and prostasome of PC-3 cells expressing PTRF. were by with PTRF expression of used for of were by growth factor in a new in the and were analyzed to determine cellular PTRF expression to the observed reduction in secreted that were by PTRF in the and were analyzed using identified of cytoskeleton as the most with a of for the and for the with J.D. of a detergent-resistant membrane from plasma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google J. D. M. N. J. A. The effect of on the proteome of detergent-resistant membrane of proteins related to cytoskeleton regulation, and cell PubMed Scopus Google Scholar), was in cytoskeletal proteins and were reduced by PTRF expression structural and regulatory proteins as and and protein of the structural cytoskeletal proteins as and were in the and not in the the that PTRF expression altered the cytoskeleton to lipid raft membrane Consistent with this, of the proteins identified in to be reduced in the by PTRF expression was a actin protein that is thought to caveolae to the actin cytoskeleton M. of as a novel for for the of membrane by the actin Biol. 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Cell 2009; PubMed Scopus Google M. N. F. The effect of cellular cholesterol on Cell 2007; PubMed Scopus Google Scholar). Caveolin-1 cholesterol and is a major of cholesterol to the plasma membrane M. J. R. F. Simons K. is a cholesterol-binding PubMed Scopus Google R.G. A for in of cholesterol from to plasma Biol. Chem. 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M. as a factor in with prostate Google Simons a of prostate cancer Full Text PDF PubMed Scopus Google Scholar). to the progression of prostate cancer, using to in advanced prostate cancer in the and results of a of a in with prostate PubMed Scopus Google Scholar). a not the to prostate Here we show that by expressing PTRF in PC-3 secretion of multiple associated with prostate cancer progression is results an novel that could a of cancer secreted by tumor of lipid raft and function by expression of PTRF. PTRF has the to the tumor microenvironment as as the cancer cells of the secreted reduced by PTRF expression on the cells as as the cancer cells. PTRF reduced the secretion of and with on total cellular that PTRF is most by the PTRF of noncaveolar caveolin-1 to caveolae. However, we the that PTRF also function of caveolae. of caveolin-1 effects on secretion from that of caveolin-1 expression secretion. expression of caveolin-1 in mouse cells Li M. 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Full Text Full Text PDF PubMed Scopus Google Scholar). that PTRF the of a of proteins to we that this a of and we observed a reduction in protein secreted by The actin cytoskeleton is with of membrane trafficking and its function is at the plasma membrane in membrane Cell Biol. 2007; PubMed Scopus Google Scholar). Intriguingly, results suggest that PTRF to the actin cytoskeleton are at ER and Golgi in secretion A of to this the Golgi is to membrane trafficking pathways, the for and Moreover, Golgi are to cellular including and plasma of membrane trafficking the on the these effects are to be by the multiple for actin at the Golgi including of and F. M. at the Golgi in Cell Biol. PubMed Scopus Google Scholar). PTRF to lipid rafts and membrane trafficking the of membrane at the plasma membrane and at the The Golgi be to these of the of between the actin cytoskeleton and lipid rafts is in membrane raft Mol. 2009; PubMed Scopus Google of lipid rafts in membrane Cell Biol. PubMed Scopus Google Scholar). lipid rafts are thought to to the actin cytoskeleton of A and M. of as a novel for for the of membrane by the actin Biol. PubMed Scopus Google Scholar). that in a A a of caveolin-1 the distribution of caveolin-1 actin of caveolin-1 at the plasma membrane, and of caveolae A. A caveolae Cell PubMed Scopus Google D. D. R. M. A is a novel in cancer cell Cell 2008; PubMed Scopus Google Scholar). We shown that PTRF expression reduced the of A and in the possibly via caveolae formation. it is that noncaveolar caveolin-1 to the cytoskeleton from caveolae. stable expression of caveolin-1 in a cancer cell line expression of A D. D. R. M. A is a novel in cancer cell Cell 2008; PubMed Scopus Google Scholar). Our data that in to caveolin-1 caveolin-1 also the of A and in lipid rafts. of the major of lipid rafts is are in PC-3 cells with prostate cell lines and the caveolin-1 cell of lipid rafts in cancer cells are correlated with by J. Full Text Full Text PDF PubMed Scopus Google Scholar). Caveolin-1 to cholesterol and its trafficking cytoskeleton and metastasis of PubMed Scopus Google The of cell cholesterol and the cytoskeleton in the between and J. Cell 2009; PubMed Scopus Google M. N. F. The effect of cellular cholesterol on Cell 2007; PubMed Scopus Google M. J. R. F. Simons K. is a cholesterol-binding PubMed Scopus Google R.G. A for in of cholesterol from to plasma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Expression of PTRF lipid raft in PC-3 cells by the formation of caveolae (5Hill M.M. Bastiani M. Luetterforst R. Kirkham M. Kirkham A. Nixon S.J. Walser P. Abankwa D. Oorschot V.M. Martin S. Hancock J.F. Parton R.G. PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function.Cell. 2008; 132: 113-124Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar). We found that PTRF expression reduced cholesterol in lipid rafts and to it partly to Moreover, by modulating cellular cholesterol we altered secretion of and that cholesterol in secretion Consistent with for a of cholesterol in shown that cholesterol the formation of regulatory and from cells is required for the formation of and from the PubMed Scopus Google Scholar), reduced and secretion in cells K. M. R. secretion of in of the the and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and the release of from PC-3 cells A. K. prostasome release from in PC-3 prostate cancer J. Biol. 2007; PubMed Scopus Google Scholar). Although and in cholesterol and cytoskeletal to in a of pathways, the to be has from a that that actin lipid raft membrane that to the M. K. A. of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the show that of membrane cholesterol using reduced actin an essential for cholesterol and lipid rafts in The of cholesterol on is cholesterol on their by with M. P. N. J. J. on via the J. PubMed Scopus Google Scholar). these and that noncaveolar caveolin-1 in PC-3 cells lipid raft which on of actin cytoskeleton and Taken together, data are with a model in which the noncaveolar caveolin-1 of proteins, in A and which are to be in caveolin-1 to actin PTRF of noncaveolar caveolin-1 to caveolae, cholesterol and lipid raft in PC-3 cells. a cytoskeletal proteins to lipid rafts are multiple the caveolin-1 microdomains of PC-3 by expression of caveolin-1 not PTRF, has these cells to a mechanism to secretion of proteases, cytokines, and growth their metastatic we show these effects were by PTRF expression. Cell is associated with cytoskeletal and membrane in for cells to actin is required for membrane and membrane with PTRF expression was shown to cell in PC-3 cells C.S. M.M. Bastiani M. Parton R.G. expression the of prostate cancer of J. Cell Biol. PubMed Scopus Google Scholar). Our to the cellular from and caveolae caveolin-1 and the for novel to caveolin-1 and its on the plasma membrane as a to Although we prostate cancer cells in this this of has the to be to tumor We for and of for of the with

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