Contactin 1 modulates pegylated arginase resistance in small cell lung cancer through induction of epithelial–mesenchymal transition

Abstract

Drug resistance is a major hurdle in the treatment of small cell lung cancer (SCLC). Previously we demonstrated the potential anticancer effect of pegylated arginase BCT-100 in SCLC cell lines and xenograft models. To facilitate future clinical application of BCT-100 in SCLC treatment, we elucidated the potential mechanisms that underlie acquired drug resistance to BCT-100. H446 and H526 SCLC cells were serially cultured in stepwise increasing concentrations of BCT-100 until stable BCT-100-resistant cell lines emerged (H446-BR and H526-BR). Compared with parent cells, H446-BR and H526-BR displayed stronger migration ability, anoikis resistance and EMT progression. Gene chip assay was employed to select three potential targets (CDH17, CNTN-1 and IGF2BP1). Silencing CNTN-1 rather than CDH17 or IGF2BP1 in H446-BR and H526-BR cells re-sensitized resistant cells to BCT-100 treatment and attenuated the epithelial–mesenchymal transition (EMT) phenotype. The AKT signaling pathway was activated in H446-BR and H526-BR cells accompanied by EMT progression, and AKT inhibitor LY294002 reversed the EMT progression in resistant cells.

Contactin 1: An Important and Emerging Oncogenic Protein Promoting Cancer Progression and Metastasis

“…CNTN1 silencing sensitized Dox-resistant PC cells and inhibited PI3K/AKT signaling in vivo. These observations are in accordance with elevated CNTN1 expression found in drug resistant SCLC cells compared with progenitor cells [57], indicating that CNTN1 may function to promote a more malignant and cancer stem cell-like characteristics with higher migration ability and potentially anoikis resistance in cancer cells.…”

“…Moreover, CNTN1 was identified as a direct downstream molecule of the vascular endothelial growth factor C (VEGFC)-VEGF receptor 3 (VEFGR3)/fms-related tyrosine kinase 4 (Flt4) axis important in lymphangiogenesis and lymphatic invasion in cancers [ 53 , 54 , 55 ]. With growing interest in the investigation of CNTN1 for its cancer related functions, CNTN1 expression was found to be upregulated in many cancers including lung [ 56 , 57 , 58 , 59 ], gastric [ 60 , 61 ], breast [ 62 ], prostate [ 63 , 64 ], stomach [ 65 ], thyroid [ 7 ], esophageal [ 66 ] cancers, hepatocellular carcinoma [ 67 , 68 ], astrocytic gliomas [ 69 ], esophageal squamous cell carcinoma (ESCC) [ 70 ], and oral squamous cell carcinoma (OSCC) [ 71 ]. Unsurprisingly, increased CNTN1 expression was found to have functional associations in promoting cancer cell progression and metastasis.…”

“…In a gene chip assay analyzing BCT-100-resistant cells in comparison to parent cells, CNTN1 was robustly upregulated and induced an EMT phenotype in resistant cells via targeting of the AKT pathways. Further functional analysis demonstrated that CNTN1 silencing re-sensitized resistant cells to BCT-100 treatment as well as attenuated the EMT phenotypes in resistant cell lines [ 57 ]. Similarly, CNTN1 expression was elevated in multidrug resistance (MDR) A549/cisplatin (A549/DDP) cells compared to its progenitor A549 lung cancer cells, and the silencing of CNTN1 rendered both cells higher cisplatin sensitivity and upregulated cisplatin-induced apoptosis, leading to inhibition of tumor invasion and metastasis [ 59 ].…”

Role of miRNA-495 and NRXN-1 and CNTN-1 mRNA Expression and Its Prognostic Importance in Breast Cancer Patients

“…CNTN-1 was upregulated in BCT-100-resistant cell lines and promoted EMT progression via the AKT pathway. e CNTN-1 gene was silenced, which resensitized resistant cells to BCT-100 treatment and reduced the EMT phenotype [42]. CNTN-1 mRNA was found to be upregulated in gastric tumors compared to noncancerous gastric samples, and this upregulation was linked to tumor size, TNM stages, metastases, and invasion [43].…”

The Role of Contactin 1 in Cancers: What We Know So Far

“…Moreover, CNTN1 promotes cell invasion, migration, and metastasis via the epithelial-mesenchymal transition (EMT) in gastric, lung, and prostate cancers and is defined as an independent prognostic predictor of gastric cancer (10)(11)(12). CNTN1 also contributes to chemoresistance in lung cancer (13)(14)(15). Additionally, CNTN1 is associated with several signal transduction pathways, such as the phosphatidylinositol 3-kinase (PI3K)/AKT, vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3), a7 nicotinic acetylcholine receptor (nAChR)/extracellular signal-regulated kinase (ERK), member A of the Ras homolog gene family (RhoA), Src-p38 mitogen-activated protein kinase (MAPK)-CCAAT/enhancerbinding protein (C/EBP) a, Notch1, and Ret protooncogene and Ret-activating protein ELE1 (RET/PTC3).…”