Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1β)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAM in an ILβ-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)-mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anti-cancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAM in PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for anti-apoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAM in the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAM in this scenario.
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Abbreviations
- IL1β:
-
interleukin 1 beta
- IL1-RA:
-
interleukin 1 receptor antagonist
- iNOS:
-
inducible nitric oxide synthase
- NO:
-
nitric oxide
- PDAC:
-
pancreatic ductal adenocarcinoma
- PI:
-
propidium iodide
- SNAP:
-
S-nitroso-N-acetyl-D,L-penicillamine
References
Arlt A, Vorndamm J, Breitenbroich M, Kalthoff H, Folsch UR, Schmidt WE et al. (2001). Inhibition of NF-kappaB activation sensitizes pancreatic tumor cells to apoptosis induced by Etoposide (VP16) or Doxorubicine. Oncogene 20: 859–868.
Arlt A, Vorndamm J, Muerkoster S, Yu H, Schmidt WE, Folsch UR et al. (2002). Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res 62: 910–916.
Arlt MJ, Novak-Hofer I, Gast D, Gschwend V, Moldenhauer G, Grunberg J et al. (2006). Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment. Cancer Res 66: 936–943.
Brummendorf T, Kenwrick S, Rathjen FG . (1998). Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations. Curr Opin Neurobiol 8: 87–97.
Castellani V, De Angelis E, Kenwrick S, Rougon G . (2002). Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J 21: 6348–6357.
Fogel M, Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Smirnov A et al. (2003). L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas. Lancet 362: 869–875.
Fukahi K, Fukasawa M, Neufeld G, Itakura J, Korc M . (2004). Aberrant expression of neuropilin-1 and -2 in human pancreatic cancer cells. Clin Cancer Res 10: 581–590.
Gast D, Riedle S, Schabath H, Schlich S, Schneider A, Issa Y et al. (2005). L1 augments cell migration and tumor growth but not beta3 integrin expression in ovarian carcinomas. Int J Cancer 115: 658–665.
Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T et al. (2005). L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 168: 633–642.
Hortsch M . (2000). Structural and functional evolution of the L1 family: are four adhesion molecules better than one? Mol Cell Neurosci 15: 1–10.
Izumoto S, Ohnishi T, Arita N, Hiraga S, Taki T, Hayakawa T . (1996). Gene expression of neural cell adhesion molecule L1 in malignant gliomas and biological significance of L1 in glioma invasion. Cancer Res 56: 1440–1444.
Kaifi JT, Strelow A, Schurr PG, Reichelt U, Yekebas EF, Wachowiak R et al. (2006a). L1 (CD171) is highly expressed in gastrointestinal stromal tumors. Mod Pathol 19: 399–406.
Kaifi JT, Zinnkann U, Yekebas EF, Schurr PG, Reichelt U, Wachowiak R et al. (2006b). L1 is a potential marker for poorly-differentiated pancreatic neuroendocrine carcinoma. World J Gastroenterol 12: 94–98.
Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G et al. (1993). p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene 8: 289–298.
Lockhart AC, Rothenberg ML, Berlin JD . (2005). Treatment for pancreatic cancer: current therapy and continued progress. Gastroenterology 128: 1642–1654.
Loers G, Chen S, Grumet M, Schachner M . (2005). Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and neuritogenesis. J Neurochem 92: 1463–1476.
Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D et al. (2005). L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol 25: 9040–9053.
Mechtersheimer S, Gutwein P, Agmon-Levin N, Stoeck A, Oleszewski M, Riedle S et al. (2001). Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 155: 661–673.
Meier F, Busch S, Gast D, Goppert A, Altevogt P, Maczey E et al. (2006). The adhesion molecule L1 (CD171) promotes melanoma progression. Int J Cancer 119: 549–555.
Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S . (2004). Tumor–stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 28: 38–44.
Moos M, Tacke R, Scherer H, Teplow D, Fruh K, Schachner M . (1988). Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin. Nature 334: 701–703.
Muerkoster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML et al. (2004). Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res 64: 1331–1337.
Schachner M . (1997). Neural recognition molecules and synaptic plasticity. Curr Opin Cell Biol 9: 627–634.
Schafer H, Arlt A, Trauzold A, Hunermann-Jansen A, Schmidt WE . (1999). The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo. Biochem Biophys Res Commun 262: 139–145.
Schneider G, Siveke JT, Eckel F, Schmid RM . (2005). Pancreatic cancer: basic and clinical aspects. Gastroenterology 128: 1606–1625.
Sebens Muerkoster S, Lust J, Arlt A, Hasler R, Witt M, Sebens T et al. (2006). Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1beta and NO lead to inactivation of caspases. Oncogene 25: 4628.
St Croix B, Kerbel RS . (1997). Cell adhesion and drug resistance in cancer. Curr Opin Oncol 9: 549–556.
Wey JS, Gray MJ, Fan F, Belcheva A, McCarty MF, Stoeltzing O et al. (2005). Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells. Br J Cancer 93: 233–241.
Acknowledgements
This study was supported by the German Research Society DFG Scha 677/7-2 (HS) and by the Medical Faculty grant of the University Kiel (HK). We thank Andreas Ludwig and Karina Reiss (Institute of Biochemistry, Christian-Albrechts-University Kiel, Germany) for their helpful discussions.
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Sebens Müerköster, S., Werbing, V., Sipos, B. et al. Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells. Oncogene 26, 2759–2768 (2007). https://doi.org/10.1038/sj.onc.1210076
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DOI: https://doi.org/10.1038/sj.onc.1210076
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