Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells

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 (IL1b)-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 ILb-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 anticancer 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 antiapoptotic 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.

Syk Tyrosine Kinase Acts as a Pancreatic Adenocarcinoma Tumor Suppressor by Regulating Cellular Growth and Invasion

“…A prior publication suggested that CD171 is not expressed in PDAC in situ 55 ; however, a subsequent report demonstrated CD171 expression in 80% of G2 and 100% of G3 PDAC tumors, 56 in agreement with our current findings. That highly aggressive PDAC cells would express CD171 is not unexpected, because CD171 mediates migratory and invasive processes in neural and melanoma cells and epithelial tumors of the breast, ovary, and colon.…”

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…L1CAM upregulates Olig2 to suppress expression of p21 WAF1/CIP1 . In addition, a number of studies showed that L1CAM is associated with chemoresistance of ovarian and pancreatic cancers (Stoeck et al, 2007;Sebens Müerköster et al, 2007;Gavert et al, 2008;Raveh et al, 2009). We have recently found that differential expression of L1CAM in GSCs contributes to therapeutic resistance.…”

The Adhesion Molecule L1CAM as a Novel Therapeutic Target for Treatment of Pancreatic Cancer Patients?

“…A study with 15 tissues of undifferentiated (anaplastic) pancreatic cancer and pancreatic carcinoma with osteoclast-like giant cells revealed L1CAM positivity in 80 % of the analysed samples (Bergmann et al, 2010a). Our group was the first who documented considerable L1CAM expression in a small series of PDAC samples (Sebens Müerköster et al, 2007). An extended analysis with 110 primary PDAC tissues, 15 lymph node and 14 liver metastases revealed tumoral L1CAM expression in 92,7 %, 80 % and 100 % of the samples, respectively (Bergmann et al, 2010b).…”

“…Stoeck et al also demonstrated that L1CAM in its membrane-bound as well as in its soluble form confers apoptosis resistance in ovarian carcinoma cells towards C2-ceramide, staurosporine, cisplatin and hypoxia. Long-term treatment with the cytostatic drug cisplatin increased L1CAM expression level in ovarian carcinoma cells m130 (Stoeck et al, 2008) which was similarly observed in PDAC cells after long-term incubation with etoposide indicating a role for L1CAM in the acquired chemoresistance of tumor cells (Sebens Müerköster et al, 2007). Immunohistochemical analyses of pancreatic tissues together with data from coculture experiments indicate that L1CAM is not only upregulated during chemotherapy but also under the influence of the cellular microenvironment.…”

“…Our group demonstrated that L1CAM plays a pivotal role in the mediation of chemoresistance of tumor cells which is a hallmark of PDAC. Thus, L1CAM expressing PDAC cell lines such as Colo357 and Panc1 responded much less towards treatment with cytostatic drugs than cells lacking L1CAM expression (Sebens Müerköster et al, 2007) and integrin has been identified as a ligand for L1CAM-mediated chemoresistance ). This chemoresistance was seen in response to drugs exerting different modes of action such as gemcitabine and etoposide indicating a broad protection against drug-induced apoptosis through L1CAM-mediated alterations in cell signalling and gene expression.…”