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Abelson interactor 1 (Abi1) im kolorektalen Karzinom

Von der synaptischen Plastizität zur Tumorzellmigration

Abelson interactor 1 (Abi1) in colorectal cancer

From synaptic plasticity to tumor cell migration

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Zusammenfassung

Hintergrund

Invasion und metastatische Aussaat von Tumorzellen sind beim kolorektalen Karzinom prognoseentscheidend. Abelson interactor 1 (Abi1), ein 65-kD-Substrat der Abelson-Tyrosinkinase, interagiert mit der Phosphatidylinositol-3-Kinase (PI3K) sowie dem heterogenen nukleären Ribonukleoprotein K (hnRNP K) und ist ein essenzielles Regulatorprotein zytoskelettärer Umbauvorgänge bei der Reifung synaptischer Verbindungen im zentralen Nervensystem und bei der Migration von Tumorzellen.

Fragestellung

Zielsetzung der Arbeit war die Darstellung des Expressionsmusters und der Rolle von Abi1 bei der Reorganisation des Zellskeletts kolorektaler Karzinomzellen.

Material und Methoden

Zum Einsatz kamen Immunhistochemie; Immunfluoreszenzmikroskopie; liposomale Transfektion; Proteinanalytik (Western Blotting).

Ergebnisse

Abi1 wird an der Invasionsfront kolorektaler Karzinome exprimiert und lokalisiert entlang lamellipodienartiger Zellausläufer kultivierter kolorektaler Karzinomzellen. Hier ist auch eine phosphorylierte Abi-1-Isoform nachzuweisen, welche nach Behandlung mit dem Tyrosinkinaseinhibitor STI571 (Glivec®) verschwindet. RNAi-Knockdown von Abi1 sowie die Gabe von STI571 verändern die zelluläre Morphologie von lamelli- hin zu filopodienartigen Zellausläufern.

Diskussion

Unsere ersten Ergebnisse deuten darauf hin, dass phosphoryliertes Abi1 eine zentrale Rolle bei der Ausbildung lamellipodienartiger Zellfortsätze als Voraussetzung für die zelluläre Migration kolorektaler Karzinomzellen spielt. Da die Phosphorylierung von Abi1 durch Applikation des Tyrosinkinaseinhibitors STI571 gehemmt werden kann, zeichnet sich hier möglicherweise eine antimetastatische Therapieoption ab, welche in weiterführenden Untersuchungen überprüft werden wird.

Abstract

Background

Invasion and metastatic dissemination of tumor cells defines the prognosis of patients with colorectal cancer (CRC). The Abelson interactor 1 (Abi1), a 65 kD substrate of the eponymous Abelson tyrosine kinase, interacts with phosphatidylinositol-3-kinase (PI3K) and heterogeneous nuclear ribonucleoprotein K (hnRNP K) and is a key regulator of cytoskeletal reorganization during synaptic maturation and cellular migration.

Aim

The aim of this study was the analysis of Abi1 expression patterns and to elucidate the role in cytoskeletal reorganization in colorectal carcinoma cells.

Material and methods

The methods used in this study were immunohistochemistry; immunofluorescence microscopy; liposomal transfection and protein analysis by Western blotting.

Results

The results showed that Abi1 is expressed at the invasive front of colorectal carcinomas and localizes to the leading edge of lamellipodia in cultured colorectal carcinoma cells. A phosphorylated isoform of Abi1 that stains positively in these microcompartments disappears after treatment with the tyrosine kinase inhibitor STI571 (Glivec®). The RNA interference (RNAi) approach knockdown of Abi1 as well as treatment with STI571 induce a shift in cellular morphology from broad lamellipodia-like to thin filopodia-like cellular protrusions.

Discussion

The initial results support a central role for phosphorylated Abi1 in the formation of lamellipodia-like cellular protrusions as a prerequisite for cellular migration of colorectal carcinoma cells. As phosphorylation of Abi1 could be pharmaceutically targeted with STI571, this indicates a possible therapeutic option to prevent the gain of a metastatic phenotype in colorectal cancer. This possibility will be further evaluated in ongoing research.

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Literatur

  1. Arnold D, Seufferlein T (2010) Targeted treatments in colorectal cancer: state of the art and future perspectives. Gut 59(6):838–858

    Article  PubMed  CAS  Google Scholar 

  2. Carpenter B, McKay M, Dundas SR et al (2006) Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer. Br J Cancer 95(7):921–927

    Article  PubMed  CAS  Google Scholar 

  3. Chen H, Wu X, Pan ZK, Huang S (2010) Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis. Cancer Res 70(23):9979–9990

    Article  PubMed  CAS  Google Scholar 

  4. Cui B, Tao J, Yang Y (2012) Studies on the expression patterns of class I PI3K catalytic subunits and its prognostic significance in colorectal cancer. Cell Biochem Biophys 62(1):47–54

    Article  PubMed  CAS  Google Scholar 

  5. Dubielecka PM, Ladwein KI, **ong X et al (2011) Essential role for Abi1 in embryonic survival and WAVE2 complex integrity. Proc Natl Acad Sci U S A 108(17):7022–7027

    Article  PubMed  CAS  Google Scholar 

  6. Innocenti M, Gerboth S, Rottner K et al (2005) Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Nat Cell Biol 7(10):969–976

    Article  PubMed  CAS  Google Scholar 

  7. Iwaya K, Oikawa K, Semba S et al (2007) Correlation between liver metastasis of the colocalization of actin-related protein 2 and 3 complex and WAVE2 in colorectal carcinoma. Cancer Sci 98(7):992–999

    Article  PubMed  CAS  Google Scholar 

  8. Jass JR, Love SB, Northover JM (1987) A new prognostic classification of rectal cancer. Lancet 1(8545):1303–1306

    Article  PubMed  CAS  Google Scholar 

  9. Kotula L (2012) Abi1, a critical molecule coordinating actin cytoskeleton reorganization with PI-3 kinase and growth signaling. FEBS Lett 586(17):2790–2794

    Article  PubMed  CAS  Google Scholar 

  10. Le Clainche C, Carlier MF (2008) Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol Rev 88(2):489–513

    Article  Google Scholar 

  11. Li Y, Clough N, Sun X et al (2007) Bcr-Abl induces abnormal cytoskeleton remodeling, beta1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway. J Cell Sci 120(Pt 8):1436–1446

    Article  PubMed  CAS  Google Scholar 

  12. Liebau S, Steinestel J, Linta L et al (2011) An SK3 channel/nWASP/Abi-1 complex is involved in early neurogenesis. PLoS one 6(3):e18148

    Article  PubMed  CAS  Google Scholar 

  13. Linder S, Wiesner C, Himmel M (2011) Degrading devices: invadosomes in proteolytic cell invasion. Annu Rev Cell Dev Biol 27:185–211

    Article  PubMed  CAS  Google Scholar 

  14. Mejillano MR, Kojima S, Applewhite DA et al (2004) Lamellipodial versus filopodial mode of the actin nanomachinery: pivotal role of the filament barbed end. Cell 118(3):363–373

    Article  PubMed  CAS  Google Scholar 

  15. Murphy DA, Courtneidge SA (2011) The ‚ins‘ and ‚outs‘ of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol 12(7):413–426

    Article  PubMed  CAS  Google Scholar 

  16. Olson MF, Sahai E (2009) The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis 26(4):273–287

    Article  PubMed  Google Scholar 

  17. Popow-Wozniak A, Wozniakowska A, Kaczmarek L et al (2011) Apoptotic effect of imatinib on human colon adenocarcinoma cells: influence on actin cytoskeleton organization and cell migration. Eur J Pharmacol 667(1–3):66–73

    Google Scholar 

  18. Proepper C, Johannsen S, Liebau S et al (2007) Abelson interacting protein 1 (Abi-1) is essential for dendrite morphogenesis and synapse formation. EMBO J 26(5):1397–1409

    Article  PubMed  CAS  Google Scholar 

  19. Proepper C, Steinestel K, Schmeisser MJ et al (2011) Heterogeneous nuclear ribonucleoprotein k interacts with Abi-1 at postsynaptic sites and modulates dendritic spine morphology. PLoS one 6(11):e27045

    Article  PubMed  CAS  Google Scholar 

  20. Ridley AJ (2011) Life at the leading edge. Cell 145(7):1012–1022

    Article  PubMed  CAS  Google Scholar 

  21. Sato M, Maruoka M, Yokota N et al (2011) Identification and functional analysis of a new phosphorylation site (Y398) in the SH3 domain of Abi-1. FEBS Lett 585(6):834–840

    Article  PubMed  CAS  Google Scholar 

  22. Shinto E, Jass JR, Tsuda H et al (2006) Differential prognostic significance of morphologic invasive markers in colorectal cancer: tumor budding and cytoplasmic podia. Dis Colon Rectum 49(9):1422–1430

    Article  PubMed  Google Scholar 

  23. Steinestel K, Bruderlein S, Steinestel J et al (2012) Expression of Abelson interactor 1 (Abi1) correlates with inflammation, KRAS mutation and adenomatous change during colonic carcinogenesis. PLoS one 7(7):e40671

    Article  PubMed  CAS  Google Scholar 

  24. Sun X, Li C, Zhuang C et al (2009) Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells. Carcinogenesis 30(12):2109–2116

    Article  PubMed  CAS  Google Scholar 

  25. Suraneni P, Rubinstein B, Unruh JR et al (2012) The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J Cell Biol 197(2):239–251

    Article  PubMed  CAS  Google Scholar 

  26. Wang C, Tran-Thanh D, Moreno JC et al (2011) Expression of Abl interactor 1 and its prognostic significance in breast cancer: a tissue-array-based investigation. Breast Cancer Res Treat 129(2):373–386

    Article  PubMed  CAS  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. K. Steinestel, F. Gläsle, S. Brüderlein, J. Steinestel, C. Pröpper, P. Möller geben an, dass kein Interessenkonflikt besteht. Alle angewandten Verfahren stehen im Einklang mit den ethischen Normen der verantwortlichen Kommission für Forschung am Menschen (institutionell und national) und mit der Deklaration von Helsinki von 1975 in der revidierten Fassung von 2008. Alle Patienten wurden erst nach erfolgter Aufklärung und Einwilligung in die Studie eingeschlossen.

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Authors and Affiliations

  1. Institut für Radiobiologie der Bundeswehr, Neuherbergstr. 11, 80937, München, Deutschland

    K. Steinestel

  2. Institut für Pathologie, Universität Ulm, Ulm, Deutschland

    K. Steinestel, F. Gläsle, S. Brüderlein & P. Möller

  3. Urologische Klinik, Universität Ulm, Ulm, Deutschland

    J. Steinestel

  4. Institut für Anatomie und Zellbiologie, Universität Ulm, Ulm, Deutschland

    C. Pröpper

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  1. K. Steinestel
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  2. F. Gläsle
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  3. S. Brüderlein
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  4. J. Steinestel
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  6. P. Möller
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Correspondence to K. Steinestel.

Additional information

Dieses Projekt wurde im Rahmen der Nachwuchsakademie 2012 der Deutschen Gesellschaft für Pathologie finanziell unterstützt. The supplement this article is part of is not sponsored by the industry.

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Steinestel, K., Gläsle, F., Brüderlein, S. et al. Abelson interactor 1 (Abi1) im kolorektalen Karzinom. Pathologe 34 (Suppl 2), 189–194 (2013). https://doi.org/10.1007/s00292-013-1810-1

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  • DOI: https://doi.org/10.1007/s00292-013-1810-1

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