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Abstract:

Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38γ motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target. ©2011 AACR.

Registro:

Documento: Artículo
Título:p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior
Autor:Rosenthal, D.T.; Iyer, H.; Escudero, S.; Bao, L.; Wu, Z.; Ventura, A.C.; Kleer, C.G.; Arruda, E.M.; Garikipati, K.; Merajver, S.D.
Filiación:Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, United States
Department of Pathology, University of Michigan, Ann Arbor, MI, United States
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, United States
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston, Boston, MA, United States
Departamento de Fisiología, Biología Molecular Y Celular, IFIBYNE-CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:actin; mitogen activated protein kinase p38; protein serine threonine kinase; Rho guanine nucleotide binding protein; article; breast cancer; cancer cell; cancer growth; cancer survival; cell motility; cell shape; controlled study; cytoskeleton; finite element analysis; human; human cell; immunoprecipitation; lymph node metastasis; metastasis; priority journal; protein analysis; protein expression; protein phosphorylation; ubiquitination; Western blotting; Animals; Breast Neoplasms; Cell Movement; Computer Simulation; Cytoskeleton; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphatic Metastasis; Mice; Mitogen-Activated Protein Kinase 12; Models, Biological; Neoplasm Invasiveness; rho GTP-Binding Proteins
Año:2011
Volumen:71
Número:20
Página de inicio:6338
Página de fin:6349
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-11-1291
Título revista:Cancer Research
Título revista abreviado:Cancer Res.
ISSN:00085472
CODEN:CNREA
CAS:Mitogen-Activated Protein Kinase 12, 2.7.1.-; RHOC protein, human; rho GTP-Binding Proteins, 3.6.5.2
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00085472_v71_n20_p6338_Rosenthal

Referencias:

  • Burstein, H.J., Polyak, K., Wong, J.S., Lester, S.C., Kaelin, C.M., Ductal Carcinoma in Situ of the Breast (2004) New England Journal of Medicine, 350 (14), pp. 1430-1441. , DOI 10.1056/NEJMra031301
  • Chang, L., Karin, M., Mammalian MAP kinase signalling cascades (2001) Nature, 410 (6824), pp. 37-40. , DOI 10.1038/35065000
  • Cuenda, A., Rousseau, S., p38 MAP-kinases pathway regulation, function and role in human diseases (2007) Biochim Biophys Acta, 1773, pp. 1358-1375
  • Wang, Y., Huang, S., Sah, V.P., Ross Jr., J., Brown, J.H., Han, J., Chien, K.R., Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family (1998) Journal of Biological Chemistry, 273 (4), pp. 2161-2168. , DOI 10.1074/jbc.273.4.2161
  • Platanias, L.C., Map kinase signaling pathways and hematologic malignancies (2003) Blood, 101 (12), pp. 4667-4679
  • Wagner, E.F., Nebreda, A.R., Signal integration by JNK and p38 MAPK pathways in cancer development (2009) Nat Rev Cancer, 9, pp. 537-549
  • Qi, X., Pohl, N.M., Loesch, M., Hou, S., Li, R., Qin, J.-Z., Cuenda, A., Chen, G., p38alpha antagonizes p38gamma activity through c-jun-dependent ubiquitin-proteasome pathways in regulating ras transformation and stress response (2007) Journal of Biological Chemistry, 282 (43), pp. 31398-31408. , http://www.jbc.org/cgi/reprint/282/43/31398, DOI 10.1074/jbc.M703857200
  • Tortorella, L.L., Lin, C.B., Pilch, P.F., ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle (2003) Biochemical and Biophysical Research Communications, 306 (1), pp. 163-168. , DOI 10.1016/S0006-291X(03)00936-7
  • Cuenda, A., Cohen, P., Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis (1999) J Biol Chem, 274, pp. 4341-4346
  • Wang, X.S., Diener, K., Manthey, C.L., Wang, S.-W., Rosenzweig, B., Bray, J., Delaney, J., Yao, Z., Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase (1997) Journal of Biological Chemistry, 272 (38), pp. 23668-23674. , DOI 10.1074/jbc.272.38.23668
  • Li, Z., Jiang, Y., Ulevitch, R.J., Han, J., The primary structure of p38gamma: A new member of p38 group of MAP kinases (1996) Biochemical and Biophysical Research Communications, 228 (2), pp. 334-340. , DOI 10.1006/bbrc.1996.1662
  • Tang, J., Qi, X., Mercola, D., Han, J., Chen, G., Essential role of p38gamma in K-ras transformation independent of phosphorylation (2005) Journal of Biological Chemistry, 280 (25), pp. 23910-23917. , DOI 10.1074/jbc.M500699200
  • Loesch, M., Chen, G., The p38 MAPK stress pathway as a tumor suppressor or more? (2008) Frontiers in Bioscience, 13 (9), pp. 3581-3593. , DOI 10.2741/2951
  • Qi, X., Tang, J., Loesch, M., Pohl, N., Alkan, S., Chen, G., p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion (2006) Cancer Research, 66 (15), pp. 7540-7547. , DOI 10.1158/0008-5472.CAN-05-4639
  • Loesch, M., Zhi, H.Y., Hou, S.W., Qi, X.M., Li, R.S., Basir, Z., p38{gamma} MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9 (2010) J Biol Chem, 285, pp. 15149-15158
  • Nocito, A., Kononen, J., Kallioniemi, O.-P., Sauter, G., Tissue microarrays (TMAS) for high-throughput molecular pathology research (2001) International Journal of Cancer, 94 (1), pp. 1-5. , DOI 10.1002/ijc.1385
  • McCabe, A., Dolled-Filhart, M., Camp, R.L., Rimm, D.L., Automated quantitative analysis (AQUA) of in situ protein expression, antibody concentration, and prognosis (2005) Journal of the National Cancer Institute, 97 (24), pp. 1808-1815. , DOI 10.1093/jnci/dji427
  • Cohen, P., The search for physiological substrates of MAP and SAP kinases in mammalian cells (1997) Trends in Cell Biology, 7 (9), pp. 353-361. , DOI 10.1016/S0962-8924(97)01105-7
  • Enslen, H., Raingeaud, J., Davis, R.J., Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6 (1998) Journal of Biological Chemistry, 273 (3), pp. 1741-1748. , DOI 10.1074/jbc.273.3.1741
  • Ladwein, M., Rottner, K., On the Rho'd: The regulation of membrane protrusions by Rho-GTPases (2008) FEBS Lett, 582, pp. 2066-2074
  • Rajah, T.T., Abuli, S.M.A., Rambo, D.J., Dmytryk, J.J., Pento, J.T., The motile behavior of human breast cancer cells characterized by time- lapse videomicroscopy [8] (1998) In Vitro Cellular and Developmental Biology - Animal, 34 (8), pp. 626-628
  • Partin, A.W., Schoeniger, J.S., Mohler, J.L., Coffey, D.S., Fourier analysis of cell motility: Correlation of motility with metastatic potential (1989) Proceedings of the National Academy of Sciences of the United States of America, 86 (4), pp. 1254-1258. , DOI 10.1073/pnas.86.4.1254
  • Nobes, C.D., Hall, A., Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia (1995) Cell, 81, pp. 53-62
  • Wheeler, A.P., Ridley, A.J., Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility (2004) Experimental Cell Research, 301 (1), pp. 43-49. , DOI 10.1016/j.yexcr.2004.08.012, PII S0014482704004793
  • Hakem, A., Sanchez-Sweatman, O., You-Ten, A., Duncan, G., Wakeham, A., Khokha, R., Mak, T.W., RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis (2005) Genes and Development, 19 (17), pp. 1974-1979. , http://www.genesdev.org/cgi/reprint/19/17/1974, DOI 10.1101/gad.1310805
  • Nielsen, T.O., Parker, J.S., Leung, S., Voduc, D., Ebbert, M., Vickery, T., A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer (2010) Clin Cancer Res, 16, pp. 5222-5232
  • Simon, C., Goepfert, H., Boyd, D., Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced M(r) 92,000 type IV collagenase secretion and in vitro invasion (1998) Cancer Research, 58 (6), pp. 1135-1139
  • Chen, L., Mayer, J.A., Krisko, T.I., Speers, C.W., Wang, T., Hilsenbeck, S.G., Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells (2009) Cancer Res, 69, pp. 8853-8861
  • Sabio, G., Arthur, J.S.C., Kuma, Y., Peggie, M., Carr, J., Murray-Tait, V., Centeno, F., Cuenda, A., p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP (2005) EMBO Journal, 24 (6), pp. 1134-1145. , DOI 10.1038/sj.emboj.7600578
  • Kim, J.H., Cho, A., Yin, H., Schafer, D.A., Mouneimne, G., Simpson, K.J., Psidin, a conserved protein that regulates protrusion dynamics and cell migration (2011) Genes Dev, 25, pp. 730-741
  • Weiner, O.D., Marganski, W.A., Wu, L.F., Altschuler, S.J., Kirschner, M.W., An actin-based wave generator organizes cell motility (2007) PLoS Biol, 5, pp. e221
  • Del, A.J.C., Meili, R., Alonso-Latorre, B., Rodriguez-Rodriguez, J., Aliseda, A., Firtel, R.A., Lasheras, J.C., Spatio-temporal analysis of eukaryotic cell motility by improved force cytometry (2007) Proceedings of the National Academy of Sciences of the United States of America, 104 (33), pp. 13343-13348. , DOI 10.1073/pnas.0705815104
  • Barnhart, E.L., Allen, G.M., Julicher, F., Theriot, J.A., Bipedal locomotion in crawling cells (2010) Biophys J, 98, pp. 933-942
  • Cano, A., Perez-Moreno, M.A., Rodrigo, I., Locascio, A., Blanco, M.J., Del Barrio, M.G., The transcription factor snail controls epithelialmesenchymal transitions by repressing E-cadherin expression (2000) Nat Cell Biol, 2, pp. 76-83
  • Yang, J., Mani, S.A., Donaher, J.L., Ramaswamy, S., Itzykson, R.A., Come, C., Savagner, P., Weinberg, R.A., Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis (2004) Cell, 117 (7), pp. 927-939. , DOI 10.1016/j.cell.2004.06.006, PII S0092867404005768
  • Chiang, A.C., Massague, J., Molecular basis of metastasis (2008) N Engl J Med, 359, pp. 2814-2823
  • Van Golen, K.L., Wu, Z.F., Qiao, X.T., Bao, L.W., Merajver, S.D., Rho, C., GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype (2000) Cancer Res, 60, pp. 5832-5838
  • Wu, M., Wu, Z.-F., Merajver, S.D., Rho proteins and cell-matrix interactions in cancer (2007) Cells Tissues Organs, 185 (1-3), pp. 100-103. , DOI 10.1159/000101309
  • Van Golen, K.L., Wei, B.L., Pan, Q., Miller, F.R., Fen, W.Z., Merajver, S.D., Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer (2002) Clinical and Experimental Metastasis, 19 (4), pp. 301-311. , DOI 10.1023/A:1015518114931
  • Clark, E.A., Golub, T.R., Lander, E.S., Hynes, R.O., Genomic analysis of metastasis reveals an essential role for RhoC (2000) Nature, 406 (6795), pp. 532-535. , DOI 10.1038/35020106
  • Ikoma, T., Takahashi, T., Nagano, S., Li, Y.-M., Ohno, Y., Ando, K., Fujiwara, T., Kosai, K.-I., A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice (2004) Clinical Cancer Research, 10 (3), pp. 1192-1200. , DOI 10.1158/1078-0432.CCR-03-0275
  • Islam, M., Lin, G., Brenner, J.C., Pan, Q., Merajver, S.D., Hou, Y., RhoC expression and head and neck cancer metastasis (2009) Mol Cancer Res, 7, pp. 1771-1780
  • Wu, M., Wu, Z.F., Rosenthal, D.T., Rhee, E.M., Merajver, S.D., Characterization of the roles of RhoC and RhoA GTPases in invasion, motility, and matrix adhesion in inflammatory and aggressive breast cancers (2010) Cancer, 116, pp. 2768-2782
  • Ridley, A.J., Rho GTPases and cell migration (2001) Journal of Cell Science, 114 (15), pp. 2713-2722
  • Rosenthal, D.T., Brenner, J.C., Merajver, S.D., Rho proteins in cancer (2010) The Rho GTPases in Cancer, pp. 29-42. , van Golen KL, editor. New York: Springer New York
  • Li, Y.-P., Chen, Y., John, J., Moylan, J., Jin, B., Mann, D.L., Reid, M.B., TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle (2005) FASEB Journal, 19 (3), pp. 362-370. , DOI 10.1096/fj.04-2364com
  • Bellei, B., Maresca, V., Flori, E., Pitisci, A., Larue, L., Picardo, M., p38 regulates pigmentation via proteasomal degradation of tyrosinase (2010) J Biol Chem, 285, pp. 7288-7299
  • Nethe, M., Hordijk, P.L., The role of ubiquitylation and degradation in RhoGTPase signalling (2010) J Cell Sci, 123, pp. 4011-4018

Citas:

---------- APA ----------
Rosenthal, D.T., Iyer, H., Escudero, S., Bao, L., Wu, Z., Ventura, A.C., Kleer, C.G.,..., Merajver, S.D. (2011) . p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior. Cancer Research, 71(20), 6338-6349.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1291
---------- CHICAGO ----------
Rosenthal, D.T., Iyer, H., Escudero, S., Bao, L., Wu, Z., Ventura, A.C., et al. "p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior" . Cancer Research 71, no. 20 (2011) : 6338-6349.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1291
---------- MLA ----------
Rosenthal, D.T., Iyer, H., Escudero, S., Bao, L., Wu, Z., Ventura, A.C., et al. "p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior" . Cancer Research, vol. 71, no. 20, 2011, pp. 6338-6349.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1291
---------- VANCOUVER ----------
Rosenthal, D.T., Iyer, H., Escudero, S., Bao, L., Wu, Z., Ventura, A.C., et al. p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior. Cancer Res. 2011;71(20):6338-6349.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1291