L1-CAM in a membrane-bound or soluble form augments protection from apoptosis in ovarian carcinoma cells
Introduction
The acquisition of apoptosis resistance is a hallmark of cancer progression. In ovarian carcinoma, this is frequently observed. Chemotherapy is important in controlling residual disease following cyto-reductive surgery and as neo-adjuvant therapy in patients with advanced disease [1]. The standard chemotherapy for advanced ovarian cancer is currently paclitaxel–carboplatin or paclitaxel–cisplatin which is routinely given together with dexamethasone, a synthetic corticoid [2]. Despite initial response to therapy, ovarian carcinomas often acquire resistance to chemotherapeutic drugs leading to tumor recurrence and frequent death of the patients [1], [2]. A better understanding of molecular mechanisms underlying chemoresistance is urgently needed.
L1 is a type I membrane glycoprotein of 200–220 kDa structurally belonging to the Ig superfamily [3]. L1 plays a crucial role in axon guidance and cell migration in the developing nervous system [4], [5]. Recent studies have also implicated L1 expression in the progression of human carcinomas. L1 expression was found on different tumors including lung cancer [6], gliomas [7], melanomas [8], [9], renal carcinoma [10], [11], and colon carcinoma [12]. We reported before that L1 is overexpressed in ovarian and endometrial carcinomas in a stage-dependent manner and that L1 expression was a predictor of poor outcome [13]. A clear mechanism by which L1 expression could contribute to the progression of human tumors is still missing. However, several recent studies have shown that overexpression of L1 can augment cell motility of carcinoma cells on extracellular matrix proteins [14], [15], [16], and invasiveness in matrigel invasion assays [12], [17], [18]. L1 expression was also found to enhance tumor growth in NOD/SCID mice [12], [19] and was found to induce L1-dependent gene expression [16], [18].
We demonstrated before that L1 is released from the cell membrane by the metalloproteases ADAM10 [14], [20] and ADAM17 [21], [22]. The soluble L1 ectodomain, as a product of L1 cleavage, is detectable in serum and ascites from ovarian carcinoma patients [13]. Soluble L1 from ascites is a potent inducer of cell migration [23]. Other functions, for instance in apoptosis protection, have not been investigated. In the present communication, we have addressed the question if expression of L1 and/or soluble L1 has an influence on apoptosis of ovarian carcinoma cells. We used cell lines stably transfected with L1 and ovarian carcinoma cell lines to study the influence of L1 expression on apoptosis induced through different apoptotic stimuli including C2-ceramide, staurosporine, cisplatin or hypoxic conditions. Our results show that expression of L1 affected apoptosis sensitivity and suggests a link between L1 expression and chemoresistance of ovarian carcinomas.
Section snippets
Cells
The ovarian carcinoma cell lines OVMz and m130 have been described before [19], [20]. The human epithelial kidney cell line HEK293 and the Chinese hamster ovary (CHO) cell line stably expressing human L1 (hL1) were established by transfection with superfect (Stratagene, Heidelberg, Germany) and selection for L1 expression with mAb L1-11A and magnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany) or sorting by FACS as described before [19], [20]. All cells were cultivated in DMEM
Expression of L1 enhances apoptosis resistance in HEK293 cells
We initially analyzed the role of L1 in apoptosis resistance using stably transfected cell lines. HEK293 and HEK293-hL1 cells were treated with C2-ceramide or staurosporine under serum-free conditions and apoptosis was analyzed by Nicoletti staining. L1-expressing cells were more resistant against apoptosis induced through both stimuli (Figs. 1B and C). 93% of the cells were still viable after 24-h treatment with C2-ceramide, compared to only 63% of wild-type HEK293 cells. Similar differences
Discussion
High-grade ovarian carcinoma is a life-threatening disease with a low 5-year survival rate. Currently, the preferred treatment regimen after surgery is combined chemotherapy comprising usually a platinum-based drug, such as cisplatin or carboplatin, coupled with paclitaxel. While this treatment course shows promising effects in a high percentage of cases, the development of chemoresistance is a hurdle that significantly reduces successful treatment outcomes. We previously reported that the
Acknowledgments
This work was supported by a grant from Deutsche Krebshilfe (Schwerpunktprogramm Migration and Invasion) and the European Community (EC-Strep Signalling & Traffic) to P.A. We thank A. Strecker and C. Math for the excellent technical assistance and Prof. Ingrid Herr for the helpful comments.
References (35)
Structural and functional evolution of the L1 family: are four adhesion molecules better than one?
Mol. Cell. Neurosci.
(2000)Neural recognition molecules and synaptic plasticity
Curr. Opin. Cell Biol.
(1997)- et al.
Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma
Eur. J. Cancer
(2002) - et al.
L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma
Cancer Lett.
(2003) - et al.
L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas
Lancet
(2003) - et al.
Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion
J. Biol. Chem.
(2004) - et al.
A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry
J. Immunol. Methods
(1991) - et al.
Role of Src kinases in the ADAM-mediated release of L1 adhesion molecule from human tumor cells
J. Biol. Chem.
(2000) - et al.
Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization
J. Biol. Chem.
(1999) - et al.
A signaling pathway from the alpha5beta1 and alpha(v)beta3 integrins that elevates bcl-2 transcription
J. Biol. Chem.
(2001)
Acquisition of chemoresistance following discontinuous exposures to cisplatin is associated in ovarian carcinoma cells with progressive alteration of FAK, ERK and p38 activation in response to treatment
Gynecol. Oncol.
Identification of potential anticancer drug targets through the selection of growth-inhibitory genetic suppressor elements
Cancer Cell.
Cancer of the ovary
N. Engl. J. Med.
Neoadjuvant chemotherapy for ovarian cancer
Oncology (Williston Park)
Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin
Nature
Expression of neural cell adhesion molecule L1 in human lung cancer cell lines
Cell Struct. Funct.
L1 expressed by glioma cells promotes adhesion but not migration
Glia
Cited by (80)
L1 Cell Adhesion Molecule and Its Soluble Form sL1 Exhibit Poor Prognosis in Primary Breast Cancer Patients
2018, Clinical Breast CancerMiR-21-3p is a positive regulator of L1CAM in several human carcinomas
2014, Cancer LettersCitation Excerpt :L1CAM is over-expressed in many human carcinomas such as pancreatic, colorectal, ovarian, endometrial, gastric and renal cancers and its expression is associated with poor patient prognosis [5–11]. Furthermore, high levels of L1CAM were found associated with increased grade of malignancy [5,12], epithelial–mesenchymal transition (EMT) [13], worse response to chemotherapy [7,14,15] and activation of the NFkB signaling pathway [16,17]. Thus, due to its ability to trigger cell motility, invasion and metastasis formation L1CAM is considered as a driver of tumor progression [18].
Sniping Cancer Stem Cells with Nanomaterials
2023, ACS NanoL1-CAM in Mucinous Ovarian Carcinomas and Borderline Tumors: Impact on Tumor Recurrence and Potential Role in Tumor Progression
2023, American Journal of Surgical PathologyIdentification of seven hypoxia-related genes signature and risk score models for predicting prognosis for ovarian cancer
2023, Functional and Integrative GenomicsADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis
2022, International Journal of Molecular Sciences