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Implication des voies de signalisation intracellulaires régulant les fonctions de la MMP-9 : action d'un nouvel agent anti-métastatique

By Mounia Bouzeghrane

Abstract

Les métalloprotéinases matricielles (MMPs) jouent un rôle crucial dans le développement malin des tumeurs. Elles dégradent la matrice extracellulaire (MEC) permettant ainsi la migration des cellules cancéreuses vers d'autres foyers. Ce processus d'invasion tumorale est appelé "processus métastasique". La MMP-9, appelée aussi gélatinase B, est fortement exprimée lors de ce processus. Son expression peut être régulée à différents niveaux via des voies de signalisation intracellulaires, notamment au niveau de l'expression du gène, mais aussi lors de la transcription, la stabilité de son ARNm, la traduction ou la sécrétion de la protéine. Des agents anti-tumoraux sont en cours de développement ciblant les différentes étapes du développement cancéreux. Le PCK3145, un peptide synthétique, dérivé de la PSP94, dirigé contre le cancer de la prostate avancé et métastasé est au stade d'essais cliniques en phase II. Ce peptide réduit chez la souris immunodéficiente la croissance des xénogreffes de tumeurs prostatiques humaines en diminuant les concentrations plasmatiques de la MMP-9. Nos travaux visent à élucider in vitro les mécanismes moléculaires impliqués dans la régulation des fonctions de la MMP-9 via l'effet anti-métastasique du PCK3145. Dans un premier temps, nous avons étudié l'interaction de la MMP-9 avec la surface de la cellule cancéreuse. Nous démontrons que le PCK3145 inhibe la sécrétion de la MMP-9 et déclenche le processus de clivage de CD44 de la surface cellulaire via une cascade de signalisation intracellulaire impliquant la GTPase RhoA. Dans un second lieu, nous avons étudié le mécanisme d'action du PCK3145 menant à l'inhibition de la sécrétion de la MMP-9. Nous démontrons que cette inhibition requiert le récepteur de la laminine à 67 kDa et est dépendante de l'activation de la voie des MAPKinases. Le PCK3145 entraine la diminution de la sécrétion de la MMP-9 via HuR, une protéine intracytoplasmique qui stabilise l'ARNm de la MMP-9 en se liant à sa séquence riche en AU. Les propriétés anti-métastasiques du PCK3145 peuvent être dirigées contre d'autres types de tumeurs, autres que le cancer de la prostate, liés à l'augmentation de la MMP-9 et à la dégradation de la MEC lors d'un processus métastasique. Par ailleurs, l'identification du mode d'action du PCK3145 via le récepteur de la laminine à 67 kDa permet de cibler des cancers dont le taux de ce récepteur est particulièrement élevé telle que la leucémie. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Cancer de la prostate, Métastase, Migration, Adhésion, MMP-9, HuR, ERK1/2, RhoA, CD44

Topics: Métalloprotéinase matricielle, Cancérogenèse, Motilité cellulaire, Métastase, Cancer de la prostate
Year: 2006
OAI identifier: oai:www.archipel.uqam.ca:2973

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Citations

  1. (2002). A Hall, Rho GTPases in cell biology, doi
  2. (2005). A Kiessling, EP Rieber, Increased p21 (ras) activity in human fibroblasts transduced with survivin enhances cell proliferation, doi
  3. (2004). A receptor for green tea polyphenol EGCG, Nat Struct Mol Biol. Il doi
  4. (2000). Altieri DC, Control of apoptosis during angiogenesis by survivin expression in endothelial cells, doi
  5. (2001). An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 doi
  6. (2003). Catechins and the treatment of breast cancer: possible utility and mechanistic targets, IDrugs. 6
  7. (2001). Caveolin-1, a putative tumour suppressor gene, doi
  8. (2005). Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme, doi
  9. (1998). Control of apoptosis and mitotic spindle checkpoint by surviving,
  10. (2004). Curcumin confers radiosensitizing effect in prostate cancer celiline PC-3, doi
  11. (2003). Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis, doi
  12. (2004). Down-regulation of Caveolin-l in gliorna vasculature: Modulation by radiotherapy,
  13. (2003). E Cohen-Jonathan Moyal, Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts, doi
  14. (2005). Epigallocatechin-3-0-gallate disrupts stress fibers and the contractile ring by reducing myosin regulatory light chain phosphorylation mediated through the target molecule 67 kDa laminin receptor, doi
  15. (2003). Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis, doi
  16. (1993). Frequency ofp53 tumor suppressor gene mutations in human primary brain tumors, doi
  17. (2002). Glioma Meta-analysis Trialists (GMT) Group, Chemotherapy in adult high grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials, doi
  18. (2002). Green tea catechins as novel antitumor and antiangiogenic compounds, Curr. Med Chem - Anti-cancer Agents.
  19. (2002). Green tea catechins inhibit vascular endotheliaI growth factor receptor phosphorylation,
  20. (1995). Inactivation of p53 is associated with decreased levels of radiation-induced apoptosis in medulloblastoma cell lines.
  21. (2001). INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis, Curr Biol. Il doi
  22. (2005). Inhibition of malignant glioma cell growth by a survivin mutant retrovirus, Hum Gene Ther. doi
  23. (2002). Inhibitory effect of epigallocatechin-3-gallate on growth and invasion in human biliary tract carcinoma cells, doi
  24. (2001). Inhibitory effect of epigallocatechin-gallate on brain tumor cell lines in vitro. doi
  25. (1994). Intrinsic and extrinsic characteristics of human tumors relevant to radiosurgery: comparative cellular radiosensitivity and hypoxic percentages,
  26. (2002). Involvement of caveolae and caveolae-like domains in signalling, cell survival and angiogenesis, doi
  27. (2003). Irradiation differentially affects substratum-dependent survival, adhesion, and invasion of glioblastoma celllines,
  28. (2005). kDa laminin receptor increases tumor aggressiveness by remodeling laminin-I,
  29. (2003). Local control of high-grade gliomas with limited volume in-adiation versus whole brain irradiation,
  30. (1998). Localization of RhoA GTPase to endothelial caveolae-enriched membrane domains, doi
  31. (2003). Localization, dynamics, and function of survivin revealed by expression of functional survivinDsRed fusion proteins in the living cell,
  32. (1994). Malignant glioma: patterns of failure following individually tailored limited volume irradiation. doi
  33. (1993). Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults, doi
  34. (1999). Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances, Mutation research. 428 doi
  35. (1996). p53-Independent Apoptosis: A Mechanism of Radiation-Induced Cell Death of Glioblastoma Cells,
  36. (1996). Phosphorylation and activation of myosin by Rho-associated kinase (Rho kinase), doi
  37. (2005). Probing the infiltrating character of brain tumors: inhibition of RhoNROK-mediated CD44 cell surface shedding from glioma cells by the green tea catechin EGCg, doi
  38. (2002). Quantitatively detennined survivin expression levels are of pronostic value in human gliomas,
  39. (2003). Radiation induced-tubulogenesis in endothelial cells is antagonized by the antiangiogenic properties of green tea polyphenol (-) epigallocatechin-3-gallate, Cancer Biol Ther.
  40. (2004). Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions, doi
  41. (2001). Radiobiological aspects, principal secondary effects,
  42. (2000). Regulation of apoptosis at cell division by p34cdc2 phosphorylation of surviving, doi
  43. (2002). Regulation of microtubule stability and mitotic progression by survivin,
  44. (2001). Rho signais to cell growth and apoptosis, doi
  45. (1998). Rho-regulated signais induce apoptosis in vitro and in vivo by a p53 independent, but Bel2 dependent pathway, doi
  46. (2002). RhoB controls the 24kDa FGF-2 induced radioresistance in HeLa cells by preventing post-mitotic cell death, doi
  47. (2004). Sensitization for tumor necrosis factor-related apoptosis inducing ligand induced apoptosis by the chemopreventive agent resveratrol, Cancer Res. doi
  48. (2004). Study of the combined effect of X-irradiation and epigallocatechin-gallate (a tea component) on the growth inhibition and induction of apoptosis in human cancer cell lines, Oncol Rep.
  49. (2001). Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma,
  50. (2004). Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms, doi
  51. (2000). Survivin initiates cell cycle entry by the competitive interaction with doi
  52. (2003). Survivin versatile modulation of cell division and apoptosis in cancer, doi
  53. (2003). Temozolomide in radio chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial,
  54. (1999). The conditional probability of survival of patients with primary malignant brain tumors: surveillance, epidemiology, and end results (SEER) data, doi
  55. (1999). The effect of extent of resection on time to tumor progression and survival in patients with glioblastoma multiforme of the cerebral hemisphere, doi
  56. (2002). The expression of Rho proteins decreases with human brain tumor progression: Potential tumor markers, Clin Exp Metastasis.
  57. (2003). Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression oftumor-associated angiogenesis, Clin Cancer Res.
  58. (2000). Three differentially expressed survivin cONA variants encode proteins with distinct antiapoptotic functions,
  59. (1999). Which glioblastoma multiforme patient will become a long-term survivor? A population-based study, doi
  60. (2004). Why three Rho proteins? RhoA, RhoB, RhoC, and cel1 motility, Exp Cell Res. doi
  61. (2004). Y y onekawa, RL Bernays, Combined thalidomide and temozolomide treatment ln patients with glioblastoma multifonne, doi

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