CNTN-1 Enhances Chemoresistance in Human Lung Adenocarcinoma Through Induction of Epithelial-Mesenchymal Transition by Targeting the PI3K/Akt Pathway

Abstract

Background/Aims: Chemoresistance has been a major obstacle to the effective treatment of lung cancer. Previously, we found that contactin-1 (CNTN-1) is related to cisplatin resistance in lung adenocarcinoma. Here, we aimed to investigate the underlying mechanism behind the role of CNTN-1 in cisplatin resistance in lung adenocarcinoma. Methods: EMT-associated phenotypes, including alterations in cellular morphology and marker (E-cadherin, N-cadherin and Vimentin) expression, were compared between A549 cells and A549/DDP cells (a cisplatin-resistant cell line of lung adenocarcinoma with abnormal CNTN-1 expression) by using real-time time PCR and Western blotting. Other methods, including CNTN-1 overexpression in A549 cells and CNTN-1 knockdown in A549/DDP cells, were also used to investigate the role of CNTN-1 in mediating the EMT phenotype and thr resulting cisplatin resistance and malignant progression of cancer cells in vitro and in vivo. Results: A549/DDP cells exhibited an EMT phenotype and aggravated malignant behaviors. CNTN-1 knockdown in A549/DDP cells partly reversed the EMT phenotype, increased drug sensitivity, and attenuated the malignant progression whereas CNTN-1 overexpression in A549 cells resulted in the opposite trend. Furthermore, the PI3K/Akt pathway was involved in the effects of CNTN-1 on EMT progression in A549/DDP cells, verified by the xenograft mouse model. Conclusion: CNTN-1 promotes cisplatin resistance in human cisplatin-resistant lung adenocarcinoma through inducing the EMT process by activating the PI3K/Akt signaling pathway. CNTN-1 may be a potential therapeutic target to reverse chemoresistance in cisplatin-resistant lung adenocarcinoma.

CNTN-1 promotes docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer

“…The PI3K/Akt signaling pathway is proved to be a promising target in cancer therapy for its contributions to cell proliferation, EMT and chemoresistance in various tumors. CNTN-1 promotes phosphorylation of Akt protein, thus increasing its activity, and an interrelation between CNTN-1 and the Akt signal has been reported [28,29]. In the present study, by silencing CNTN-1 in PCa, PI3K/ Akt signaling, EMT and Dox resistance were distinctly inhibited, and the effect of CNTN-1 knockdown was partially abolished by using the PI3K activator IGF-1 at the same time.…”

“…Recently, CNTN-1 was demonstrated to promote the development of various cancers including lung, squamous, hepatocellular, gastric and prostate cancer [30,[37][38][39][40][41]. Aberrant CNTN-1 was discovered to aggravate tumor invasion, metastasis, EMT and chemoresistance in lung cancer [29]. In PCa, CNTN-1 exacerbated in vitro cell invasion and in vivo tumor growth and lung metastasis in PCa [30].…”

“…As a consequence, new measures to restrain EMT or promote mesenchymalepithelial transition (MET) are essential to enhance the therapeutic effect of PCa. As one of the neuronal cell adhesion molecules, contactin-1 (CNTN-1), which is composed of N-CAM, L1 and Nr-CAM, belongs to the immunoglobulin superfamily [26], and has been identified as a tumor oncogene, which is found to be up-regulated and involved in several cancers including gastric [27], lung [28,29] and prostate cancer [30,31]. Moreover, emerging evidence has indicated that CNTN-1 is associated with cisplatin chemo-resistance in lung cancer [29], suggesting that CNTN-1 may serve as a potential drug resistance-associated tumor gene.…”

Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial–mesenchymal transition

“…Evidence shows the ability for metastasis and invasion of cancer cells after EMT is remarkably enhanced, and these mesenchymal-like cells are strongly resistant to targeted drugs or radio- or chemotherapy. 63 – 65 Tumor cells after EMT express high levels of stem surface markers, indicating that these cells have become stem-like cells. 66 – 68 One interesting study revealed that breast CSCs originate from the fusion of M2-TAMs and breast cancer cells; these hybrid cells overexpress mesenchymal-associated genes and stemness markers.…”

miR-1260b Activates Wnt Signaling by Targeting Secreted Frizzled-Related Protein 1 to Regulate Taxane Resistance in Lung Adenocarcinoma

“…Several potential chemoresistance mechanisms involving EMT have been suggested (34,35). It is well-known that EMT occurs during tumor migration and invasion, and facilitates tumor progression (36).…”