Synthetic Triterpenoids Target the Arp2/3 Complex and Inhibit Branched Actin Polymerization

Synthetic triterpenoids are anti-tumor agents that affect numerous cellular functions including apoptosis and growth inhibition. Here, we used mass spectrometric and protein array approaches and uncovered that triterpenoids associate with proteins of the actin cytoskeleton, including actin-related protein 3 (Arp3). Arp3, a subunit of the Arp2/3 complex, is involved in branched actin polymerization and the formation of lamellipodia. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-Im and CDDO-Me were observed to 1) inhibit the localization of Arp3 and actin at the leading edge of cells, 2) abrogate cell polarity, and 3) inhibit Arp2/3-dependent branched actin polymerization. We confirmed our drug effects with siRNA targeting of Arp3 and observed a decrease in Rat2 cell migration. Taken together, our data suggest that synthetic triterpenoids target Arp3 and branched actin polymerization to inhibit cell migration. Synthetic triterpenoids are anti-tumor agents that affect numerous cellular functions including apoptosis and growth inhibition. Here, we used mass spectrometric and protein array approaches and uncovered that triterpenoids associate with proteins of the actin cytoskeleton, including actin-related protein 3 (Arp3). Arp3, a subunit of the Arp2/3 complex, is involved in branched actin polymerization and the formation of lamellipodia. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-Im and CDDO-Me were observed to 1) inhibit the localization of Arp3 and actin at the leading edge of cells, 2) abrogate cell polarity, and 3) inhibit Arp2/3-dependent branched actin polymerization. We confirmed our drug effects with siRNA targeting of Arp3 and observed a decrease in Rat2 cell migration. Taken together, our data suggest that synthetic triterpenoids target Arp3 and branched actin polymerization to inhibit cell migration. IntroductionCell migration is crucial in many physiological processes such as embryogenesis, cell differentiation, cell renewal, and immune system responses. During these processes, cells undergo highly regulated and coordinated cell migration to enable growth or repair of cells. Cell migration is also important in the metastasis of tumor cells. Indeed, it is a hallmark of the most aggressive and advanced epithelial tumors prior to entering the metastatic stage. These tumor cells often undergo epithelial to mesenchymal transition and migrate in a deregulated manner. As a result, they invade other tissues and take over the host organism (1Ozdamar B. Bose R. Barrios-Rodiles M. Wang H.R. Zhang Y. Wrana J.L. Science. 2005; 307: 1603-1609Crossref PubMed Scopus (708) Google Scholar), causing 90% of cancer-related deaths (2Mehlen P. Puisieux A. Nat. Rev. Cancer. 2006; 6: 449-458Crossref PubMed Scopus (1346) Google Scholar).Cell migration occurs through the coordination of numerous cellular proteins. This process includes directional sensing of cells, anchorage of cells at the leading edge, and the reorganization of different components in the cell to assist in cell movement. The orientation of cell movement is largely dependent on the reorganization of the cytoskeleton, which consists of microtubules, intermediate filaments, and actin cytoskeleton. Although microtubules, intermediate filaments, and leading edge proteins are pivotal in the structure and organization of migrating cells, the actin cytoskeleton also plays an essential role in cell polarity and cell migration. For instance, actin is involved in the formation of the lamellipodia and filopodia, which are membrane and finger-like projections, respectively, at the leading edge of migrating cells. Both lamellipodia and filopodia are important for directional and environmental sensing even though they may be formed through two distinct actin-assembly machineries with different actin dynamic properties (3Le Clainche C. Carlier M.F. Physiol. Rev. 2008; 88: 489-513Crossref PubMed Scopus (624) Google Scholar). Lamellipodia are formed by actin-related protein 2/3 (Arp2/3) 2The abbreviations used are: Arpactin-related proteinn-WASpneural Wiskott-Aldrich Syndrome proteinTRAILtumor necrosis factor-related apoptosis-inducing ligandCDDO2-cyano-3,12-dioxooleana-1,9-dien-28-oic acidb-CDDObiotinylated CDDOb-CDDO-Mebiotinylated CDDO-MeCDDO-ImCDDO-imidazolideDMSOdimethyl sulfoxideDICdifferential interference contrast. complexes through branched actin nucleation, whereas filopodia are formed by formin by progressive unbranched actin nucleation. Although the processes of the two are similar in that they are both activated by small Rho GTPases and a nucleation-promoting factor is required for actin polymerization, the key effectors that enable these processes are distinct. For instance, Cdc42 activates neural Wiskott-Aldrich Syndrome protein (n-WASp), which in turn promotes nucleation and branched actin polymerization, whereas the activation of the RhoA induces formin-dependent unbranched actin polymerization. Interestingly, Rac1, another small Rho GTPase, has been shown to be involved both indirectly and directly in branched and unbranched actin polymerization, respectively. The understanding of the two distinct actin polymerization processes is crucial in understanding how cell migration is coordinated with other key cellular processes.Because cell migration is a precursor event of cancer metastasis, chemotherapeutic agents that block cell migration have been an important focus in the field of cancer chemotherapy. Recently, the parental synthetic oleanane triterpenoid (CDDO) and its more potent derivatives (CDDO-Im and CDDO-Me) have been suggested to be promising therapeutic agents. Specifically, CDDO and its and derivatives have been shown to inhibit tumor growth and apoptosis R. C. 2006; PubMed Scopus Google M. M. 2005; PubMed Scopus Google Google A. Y. 2008; PubMed Scopus Google R. 2006; PubMed Scopus Google Nat. Rev. Cancer. PubMed Scopus Google M. M. M. PubMed Scopus Google M. PubMed Scopus Google M. M. 2006; PubMed Scopus Google C. PubMed Scopus Google C. M. M. 2006; PubMed Scopus Google Y. PubMed Google 2006; PubMed Scopus Google M. M. 6: PubMed Scopus Google 2006; PubMed Scopus Google Scholar). CDDO and its derivatives also the Y. PubMed Scopus Google Wang Y. PubMed Scopus Google Wang Y. PubMed Scopus Google Wang Y. PubMed Scopus Google Y. M. Google M. Google and are potent of and at two and which are with in many Wang Y. Google Scholar). These have been in including M. M. M. PubMed Scopus Google A. M. M. R. PubMed Scopus Google Cancer. 2006; PubMed Scopus Google PubMed Scopus Google 2006; PubMed Scopus Google Scholar), M. M. 2006; PubMed Scopus Google M. M. M. PubMed Scopus Google Y. P. A. Cell Google M. R. M. 2005; PubMed Scopus Google M. Wang M. M. PubMed Scopus Google M. P. M. M. PubMed Scopus Google A. PubMed Scopus Google Scholar), Y. PubMed Scopus Google Scholar), Y. PubMed Scopus Google Scholar), Y. P. R. PubMed Scopus Google Scholar), and cancer cell of the R. 2006; PubMed Scopus Google R. P. PubMed Scopus Google R. PubMed Scopus Google P. 6: PubMed Scopus Google P. R. PubMed Scopus Google Scholar), M. M. M. PubMed Scopus Google M. M. Google R. M. M. 2005; PubMed Scopus Google M. Zhang M. M.F. M. M. 2006; PubMed Scopus Google Scholar), B. M. M. PubMed Scopus Google Scholar), M. R. M. M. 2005; PubMed Scopus Google Scholar), M. M. 2005; PubMed Scopus Google Scholar), and Google Scholar). have been shown to cells A. Y. M. PubMed Scopus Google and necrosis factor-related apoptosis-inducing cancer cells to apoptosis R. M. M. 2005; PubMed Scopus Google M. M. M. PubMed Scopus Google Scholar). even though have shown that is highly in cancer cell and for tumor growth and the of the synthetic triterpenoids on cell migration and metastasis has been shown to target proteins at the leading edge of the cells and the of the through a that agents such as C. Wrana J.L. 2008; PubMed Scopus Google Scholar). The to in how other derivatives of CDDO may affect cell have shown that cell migration and the of the through a distinct agents such as C. Wrana J.L. 2008; PubMed Scopus Google Scholar). the of and we to through the of mass and protein array For these we to synthetic triterpenoids that be used for the and of proteins. the of the of its we used the CDDO and the in our CDDO-Me is a as it has been shown to be as potent as the in many cellular A. Y. 2008; PubMed Scopus Google C. PubMed Scopus Google M. M. 6: PubMed Scopus Google M. Google R. A. PubMed Scopus Google Scholar), with the CDDO parental Cell and to the of to the of the CDDO-Me in cell migration by its of cell migration with and cells Rat2 were to a by the cells of the of the The cells were with of synthetic triterpenoids were at and of at to the of cell migration be by and CDDO-Me We observed that cell migration in the of whereas cell migration in the of or CDDO-Me Indeed, at the of cell migration in and cells to whereas the of migration in cells with the and the parental CDDO is at in cell migration and used as a in cell the were and the cells were with for an We observed that cells with CDDO and and CDDO-Me and the This confirmed that CDDO is potent the and These more potent triterpenoids also in similar to cell that CDDO to the leading edge of migrating cells C. Wrana J.L. 2008; PubMed Scopus Google and may target proteins involved in the polarity at cellular We CDDO-Me also the leading edge of migrating cells We observed that to the leading edge of migrating cells, similar to CDDO These that the localization of CDDO and CDDO-Me is and target the leading edge of migrating cells. Rat2 were to a for to cell and cells were and with and CDDO or CDDO-Me by and Cell were with The of with or at the leading edge of migrating cells is The the of cell movement. are of and CDDO-Me in cellular localization and of cell we used to synthetic triterpenoid two approaches the we a mass and proteins that with or were by by and for This mass with a protein array which The with or CDDO-Me by The proteins were and proteins that the were as two different approaches and by proteins involved in organization and cell migration were of proteins. Rat2 were with or and with and were and proteins that were in were the and by mass of cell proteins mass and protein array Rat2 were with or and with were by and for proteins and of protein were also for and actin and shown that the are also cellular we cells with or the cells, and or with and the with and actin with M. 2006; PubMed Scopus Google Scholar), we that with the and also to with to a Interestingly, a of the cytoskeleton, and actin-related protein 3 were also to associate with and with the Arp2/3 and inhibit branched actin polymerization. Arp2/3 protein with or for by with for by and with also with Arp3 and shown Rat2 were with or for by of to proteins that with the of the synthetic by for Arp3 with of protein were also for Arp3 and shown Rat2 were with or CDDO-Me for by with The were to and with and of were also for and Arp3 and shown that the of Arp3 and is by triterpenoid Arp2/3 and the of were in the or of triterpenoids and with The were to and with and of the also for and Arp3 and shown that the of Arp3 and is by triterpenoid actin for on to actin actin or actin in the of Arp2/3 (Arp2/3) and of protein were with or of or CDDO-Me polymerization by and as of proteins in our approaches were of the Rho Rho GTPases are a of involved in the of cell polarity and orientation of the cell migration. are regulated by which the activation of small Rho and by which the protein its that triterpenoids affect the of or more of the numerous factor and proteins M. M. Cell PubMed Scopus Google by directly the of Rac1, or We observed that in Cdc42 and RhoA and Rac1, and RhoA that to these small GTPases and CDDO-Me by our to that are of GTPases and the cytoskeleton and cell that the actin cytoskeleton. are two different actin machineries involved in the formation of actin with different properties in different of migrating cells. Arp2/3 is involved in the of branched actin at the leading edge of migrating cells, whereas formin is involved in the formation of unbranched actin such as (3Le Clainche C. Carlier M.F. Physiol. Rev. 2008; 88: 489-513Crossref PubMed Scopus (624) Google Scholar). We have observed that the actin are largely by triterpenoid C. Wrana J.L. 2008; PubMed Scopus Google Scholar), we synthetic triterpenoids have on branched actin formation by actin and Arp2/3 is a of and and two actin-related proteins and have shown that Arp3 is involved in the nucleation process of branched actin formation (3Le Clainche C. Carlier M.F. Physiol. Rev. 2008; 88: 489-513Crossref PubMed Scopus (624) Google Scholar). We to Arp3 a target of the synthetic triterpenoid through by both Arp2/3 protein as as in Rat2 cells protein with or CDDO-Me for and with by with that Arp3 with CDDO-Me in in cells, we Rat2 with and for Arp3 These two approaches confirmed our and that Arp3 with the formation of branched actin to Arp2/3 and with actin also Indeed, by Arp2/3 complexes that it the nucleation process for branched actin polymerization. we that the triterpenoid may inhibit cell migration by targeting Arp3 directly and the of Arp3 with actin were Rat2 were with or with and for and Arp3 that Arp3 with both and actin or CDDO-Me These suggest that the Arp3 and is by the synthetic triterpenoids in cells or in that of the Arp2/3 are proteins to the of branched actin polymerization in the of and We the of actin polymerization in the of actin or actin and the of and in the or of different of and CDDO-Me We observed that the of actin polymerization by both CDDO-Me and with of the of actin polymerization by both triterpenoids were to actin polymerization actin polymerization in the of and data suggest that triterpenoids target branched actin the cellular localization of Arp3 also by triterpenoid Rat2 were and cells were to and a leading edge with or The cells were and for Arp3, and We observed that Arp3 and at the leading edge of cells in the of with both proteins were the leading edge and the of the cell CDDO-Me effects as the triterpenoids affect the localization of Arp3 and at the leading edge of cells. Rat2 were and for at to cell polarity and with or CDDO-Me for an The cells were and with for and The were in the the cells. and proteins at the leading edge of migrating cells are by and respectively. The the of proteins. the of cellular movement. to the leading edge of migrating cells. of cells or at the leading edge of migrating cells and as localization at the leading edge of 3 a and of Arp3 and with that the of triterpenoids to Arp3 and branched we the of the synthetic triterpenoids on and are of the most and unbranched actin in the cell and is a of Rat2 cells were and with the synthetic triterpenoids for and and were used to for and respectively. We that the of both and were by or CDDO-Me with our in branched actin at the leading edge of migrating cells the with triterpenoids and CDDO-Me affect or branched actin at the leading edge of migrating cells. 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PubMed Scopus Google Scholar), were the of Arp2/3 A. R. PubMed Scopus Google The structure used for the been with a small to a in We the The two to of in the in two different which were the in of to a of of these to the and observed in the the of the to an with a of This for to the for the by and A. R. PubMed Scopus Google we observed that the triterpenoid CDDO-Me to Arp3 in the and The shown in has a of and of the for the the and Arp3 including of the which has an to the acid in of the in to the on Arp3, with an even of is that the for both CDDO-Me and of the triterpenoid to the is the of for the used for the Arp2/3 Rat2 and the is with of the CDDO-Me As be in the that CDDO-Me is to to the of which in turn is to the of in the structure A. R. PubMed Scopus Google Scholar). with Arp3 both CDDO-Me and a in the to which the to The for CDDO-Me with is with the of CDDO-Me required for of CDDO-Me to the Arp2/3 The and of the Arp2/3 A. R. 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PubMed Scopus Google Scholar). of with Arp2/3 with CDDO-Me in the or of of CDDO-Me or The Arp3 with for and with Arp3 of the also with Arp3 and shown on the that CDDO-Me and to the in Arp3, were with and CDDO-Me as a of CDDO-Me or the of Arp3 that with This is with our that that and CDDO-Me in the of Arp3 Cell and Cell the of Arp3 also abrogate cell we cells with of We observed that to inhibit cell migration by The which to to Arp3 inhibit its cell migration at the of the cells with the Arp3 that the cells a and the of over the cells This that the cells may undergo and in the of an Arp3 cell migration. Rat2 were to a and with or for were at the of the and of at The the leading edge of migrating cells. cells were with of or and Cell migration and as cell migration of Arp3 3 we cells with affect branched actin polymerization in a similar to the Rat2 were and cells were to to a leading edge with or The cells were and for Arp3, and We observed that Arp3 and at the leading edge of cells in the of both proteins were the leading edge and the of the cell We also observed that at the leading edge of cells as as actin were in the cells that the of branched actin polymerization cell polarity Taken together, our suggest that synthetic triterpenoids target Arp2/3-dependent actin polymerization, which to the of cell the localization of Arp3 and at the leading edge of cells. Rat2 were and for at to cell polarity and with or for an The cells were and with for and The were in the the cells. and proteins at the leading edge of migrating cells are by and respectively. The the of proteins. the of cellular movement. to the leading edge of migrating cells. of cells or at the leading edge of migrating cells and as localization at the leading edge of 3 a and of Arp3 and with affect or branched actin at the leading edge of migrating cells. Rat2 were and for at to cell polarity and with or for an The cells were and with for and The were in the the cells. branched and actin proteins at the leading edge of migrating cells are by and respectively. The the of proteins. the of cellular movement. to the leading edge of migrating cells. of cells actin at the leading edge of migrating cells and as localization at the leading edge of 3 migration plays an essential role in immune and cellular it is the precursor event prior to most advanced cancer The of cell migration it to its of in the of an that is of different of the in is to the of targeting cell migration to block tumor cells migrating and other of the we that synthetic which are at apoptosis and are also at cell migration. We observed that cell migration is by CDDO-Me and in a with most apoptosis over We also that Arp3 a protein Arp3 is an important subunit of the Arp2/3 complex, which is involved in the nucleation process of branched actin polymerization. Interestingly, the of triterpenoids to inhibit branched actin polymerization in the to inhibit cell migration This may the that the of proteins in the or that are other triterpenoid in the cell that have to be This is by our that the cytoskeleton is by C. Wrana J.L. 2008; PubMed Scopus Google of Arp2/3 siRNA has been observed to cell migration that the triterpenoids target Arp3 and inhibit cell migration by branched actin polymerization actin polymerization is essential for the formation of the lamellipodia at the leading edge of migrating cells, which in turn for cell migration. the of branched actin polymerization by synthetic triterpenoids Arp3 may a for which agents may be to cell migration and we also the of small Rho GTPases be by triterpenoid Although small Rho GTPases a role in cell they to be triterpenoid Interestingly, we that by whereas the of the other Rho GTPases were This is to with to the of cell migration. We that be to a of another that has to be Arp2/3 have been by and A. R. PubMed Scopus Google Scholar). These to different of the Arp2/3 complex, its Specifically, and and Arp3 an for nucleation. and associate with Arp3 at its in a that nucleation of branched This on how the of Arp2/3 activation of the Arp2/3 may be to the synthetic Indeed, we observed that CDDO-Me to Arp2/3 in the as and in This with Arp3 cell migration and polarity We that and CDDO-Me inhibit Arp2/3 in a similar as the Arp3 Taken together, that a of and branched actin are involved in of cell migration. IntroductionCell migration is crucial in many physiological processes such as embryogenesis, cell differentiation, cell renewal, and immune system responses. During these processes, cells undergo highly regulated and coordinated cell migration to enable growth or repair of cells. Cell migration is also important in the metastasis of tumor cells. Indeed, it is a hallmark of the most aggressive and advanced epithelial tumors prior to entering the metastatic stage. These tumor cells often undergo epithelial to mesenchymal transition and migrate in a deregulated manner. As a result, they invade other tissues and take over the host organism (1Ozdamar B. Bose R. Barrios-Rodiles M. Wang H.R. Zhang Y. Wrana J.L. Science. 2005; 307: 1603-1609Crossref PubMed Scopus (708) Google Scholar), causing 90% of cancer-related deaths (2Mehlen P. Puisieux A. Nat. Rev. Cancer. 2006; 6: 449-458Crossref PubMed Scopus (1346) Google Scholar).Cell migration occurs through the coordination of numerous cellular proteins. This process includes directional sensing of cells, anchorage of cells at the leading edge, and the reorganization of different components in the cell to assist in cell movement. The orientation of cell movement is largely dependent on the reorganization of the cytoskeleton, which consists of microtubules, intermediate filaments, and actin cytoskeleton. Although microtubules, intermediate filaments, and leading edge proteins are pivotal in the structure and organization of migrating cells, the actin cytoskeleton also plays an essential role in cell polarity and cell migration. For instance, actin is involved in the formation of the lamellipodia and filopodia, which are membrane and finger-like projections, respectively, at the leading edge of migrating cells. Both lamellipodia and filopodia are important for directional and environmental sensing even though they may be formed through two distinct actin-assembly machineries with different actin dynamic properties (3Le Clainche C. Carlier M.F. Physiol. Rev. 2008; 88: 489-513Crossref PubMed Scopus (624) Google Scholar). Lamellipodia are formed by actin-related protein 2/3 (Arp2/3) 2The abbreviations used are: Arpactin-related proteinn-WASpneural Wiskott-Aldrich Syndrome proteinTRAILtumor necrosis factor-related apoptosis-inducing ligandCDDO2-cyano-3,12-dioxooleana-1,9-dien-28-oic acidb-CDDObiotinylated CDDOb-CDDO-Mebiotinylated CDDO-MeCDDO-ImCDDO-imidazolideDMSOdimethyl sulfoxideDICdifferential interference contrast. complexes through branched actin nucleation, whereas filopodia are formed by formin by progressive unbranched actin nucleation. Although the processes of the two are similar in that they are both activated by small Rho GTPases and a nucleation-promoting factor is required for actin polymerization, the key effectors that enable these processes are distinct. For instance, Cdc42 activates neural Wiskott-Aldrich Syndrome protein (n-WASp), which in turn promotes nucleation and branched actin polymerization, whereas the activation of the RhoA induces formin-dependent unbranched actin polymerization. Interestingly, Rac1, another small Rho GTPase, has been shown to be involved both indirectly and directly in branched and unbranched actin polymerization, respectively. The understanding of the two distinct actin polymerization processes is crucial in understanding how cell migration is coordinated with other key cellular processes.Because cell migration is a precursor event of cancer metastasis, chemotherapeutic agents that block cell migration have been an important focus in the field of cancer chemotherapy. Recently, the parental synthetic oleanane triterpenoid (CDDO) and its more potent derivatives (CDDO-Im and CDDO-Me) have been suggested to be promising therapeutic agents. Specifically, CDDO and its and derivatives have been shown to inhibit tumor growth and apoptosis R. C. 2006; PubMed Scopus Google M. M. 2005; PubMed Scopus Google Google A. Y. 2008; PubMed Scopus Google R. 2006; PubMed Scopus Google Nat. Rev. Cancer. PubMed Scopus Google M. M. M. PubMed Scopus Google M. PubMed Scopus Google M. M. 2006; PubMed Scopus Google C. PubMed Scopus Google C. M. M. 2006; PubMed Scopus Google Y. PubMed Google 2006; PubMed Scopus Google M. M. 6: PubMed Scopus Google 2006; PubMed Scopus Google Scholar). CDDO and its derivatives also the Y. PubMed Scopus Google Wang Y. PubMed Scopus Google Wang Y. PubMed Scopus Google Wang Y. PubMed Scopus Google Y. M. Google M. Google and are potent of and at two and which are with in many Wang Y. Google Scholar). These have been in including M. M. M. PubMed Scopus Google A. M. M. R. PubMed Scopus Google Cancer. 2006; PubMed Scopus Google PubMed Scopus Google 2006; PubMed Scopus Google Scholar), M. M. 2006; PubMed Scopus Google M. M. M. PubMed Scopus Google Y. P. A. Cell Google M. R. M. 2005; PubMed Scopus Google M. Wang M. M. PubMed Scopus Google M. P. M. M. PubMed Scopus Google A. PubMed Scopus Google Scholar), Y. PubMed Scopus Google Scholar), Y. PubMed Scopus Google Scholar), Y. P. R. PubMed Scopus Google Scholar), and cancer cell of the R. 2006; PubMed Scopus Google R. P. PubMed Scopus Google R. PubMed Scopus Google P. 6: PubMed Scopus Google P. R. PubMed Scopus Google Scholar), M. M. M. PubMed Scopus Google M. M. Google R. M. M. 2005; PubMed Scopus Google M. Zhang M. M.F. M. M. 2006; PubMed Scopus Google Scholar), B. M. M. PubMed Scopus Google Scholar), M. R. M. M. 2005; PubMed Scopus Google Scholar), M. M. 2005; PubMed Scopus Google Scholar), and Google Scholar). have been shown to cells A. Y. M. PubMed Scopus Google and necrosis factor-related apoptosis-inducing cancer cells to apoptosis R. M. M. 2005; PubMed Scopus Google M. M. M. PubMed Scopus Google Scholar). even though have shown that is highly in cancer cell and for tumor growth and the of the synthetic triterpenoids on cell migration and metastasis has been shown to target proteins at the leading edge of the cells and the of the through a that agents such as C. Wrana J.L. 2008; PubMed Scopus Google Scholar). The to in how other derivatives of CDDO may affect cell migration.

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