title: Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells.
abstract: BACKGROUND
  The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer.
  
  
  RESULTS
  In 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix.
  
  
  CONCLUSIONS
  Our data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer.
authors.affiliation: Bundeswehr Institute of Radiobiology, Neuherbergstr, 11, 80937 Munich, Germany. konrad@steinestel.com.
authors.forename: Konrad
authors.initials: K
authors.lastname: Steinestel
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.forename: Julie
authors.initials: J
authors.lastname: Steinestel
authors.forename: Klaus
authors.initials: K
authors.lastname: Kraft
authors.forename: Christian
authors.initials: C
authors.lastname: Pröpper
authors.forename: Viktor
authors.initials: V
authors.lastname: Meineke
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
mesh_terms: D000199:Actins / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage; D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011743:Pyrimidines / Q000008:administration & dosage; D018631:ras Proteins / Q000235:genetics
chemical_list: C513733:ABI1 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D004265:DNA Helicases; C080359:CHD1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins