| Autor: |
Meier C; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., La Rocca G; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Nawrot V; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Fißlthaler B; Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University Frankfurt, 60590 Frankfurt, Germany., Overby SJ; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Hourfar K; German Red Cross Blood Service Baden-Württemberg-Hessen, Institute for Transfusion Medicine and Immunohematology, Goethe University Frankfurt, 60590 Frankfurt, Germany., Plotz G; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Seidl C; German Red Cross Blood Service Baden-Württemberg-Hessen, Institute for Transfusion Medicine and Immunohematology, Goethe University Frankfurt, 60590 Frankfurt, Germany., Ziegler P; Dr. Senckenberg Institute of Pathology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Wild P; Dr. Senckenberg Institute of Pathology, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Zeuzem S; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany., Brieger J; Department of Otorhinolaryngology, University Medical Center Mainz, 55131 Mainz, Germany., Jäger E; Department of Oncology and Hematology, Hospital Nordwest, 60488 Frankfurt, Germany., Battmann A; Department of Pathology, Hospital Nordwest, 60488 Frankfurt, Germany., Brieger A; Biomedical Research Laboratory, Medical Clinic 1, University Hospital, Goethe University Frankfurt, 60590 Frankfurt, Germany. |
| Abstrakt: |
Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RAS - mediated RAF / MEK / ERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients. |
