<p>Tizanidine (Hydrochloride) Inhibits A549 Lung Cancer Cell Proliferation and Motility Through Regulating Nischarin</p>

Abstract

Purpose: Tizanidine hydrochloride (TZN) is a centrally acting α 2-adrenergic agonist. In this study, we aimed to explore the role of TZN on human lung cancer and to elucidate its underlying mechanisms. Methods: The effect of TZN treatment in A549 cell proliferation, migration, invasion and apoptosis was evaluated by CCK8, transwell and flow cytometer assays. The expression of apoptosis-related proteins and the activation of AKT and Wnt3a/β-catenin pathways were detected by Western blot. From the data of DrugBank, TZN could act as an agonist to target Nischarin in humans. We next investigated the function of Nischarin receptor in lung cancer and its role in the anti-tumor activity of TZN. Results: The treatment of TZN inhibited the proliferation, migration and invasion of A549 cells, and induced apoptosis. These results were further confirmed by that TZN treatment increased the Bax/Bcl-2 ratio in A549 cells. We also observed that TZN treatment changed the expression and phosphorylation of proteins of AKTand Wnt3a/β-catenin signaling pathway members. By bioinformatics analysis, we found that Nischarin was down-regulated in human lung cancer tissues and patients with high Nischarin expression had a better survival. Moreover, Nischarin functioned as a tumor suppressor in the survival and metastasis of A549 cells through the regulation of AKT and Wnt3a/β-catenin pathways. Knockdown of Nischarin promoted the proliferation, invasion, migration of A549 cells and inhibited the apoptosis, which were reversed by the TZN treatment. Conclusion: Summary, our data revealed that treatment of TZN inhibited the growth of lung cancer cell line A549 and may be used as a novel strategy for lung cancer therapy.

MicroRNA-2355-5p Promotes the Proliferation of Head and Neck Squamous Cell Carcinoma via Suppressing NISCH Expression

“…In ovarian cancer, promoter hypermethylation-induced NISCH silence-promoted cell cycle progression through the focal adhesion kinase (FAK) signal [22]. Besides, a previous study indicated that tizanidine hydrochloride inhibited A549 cell proliferation and mobility via upregulating the NISCH expression [24]. All the aforementioned results support the results of our study.…”

“…e expression of NISCH is closely related to tumorigenesis, progression, and poor prognosis in cancers, including breast, lungs, and ovarian cancers [22,24,37,38]. A series of publications reported that NISCH was a tumor-suppressive factor in breast cancer, and NISCH-expressing cells delivered exosomes that suppress breast cancer cell growth and mobility [21,37,39,40].…”

“…Differences in gene expression between groups were assessed using the Student's t-test. Programs of microT (20)(21)(22) and miRmap (23,24) were employed for the prediction of candidate targets for miR-2355-5p using the Encyclopedia of RNA Interactomes (ENCORI) online tools [26,27], followed by the removal of miRNA-target pairs without crosslinking immunoprecipitation (CLIP) or Degradome data. e Pearson correlation coefficient (PCC) value between each pair was subsequently calculated with the TCGA-HNSC data.…”

“…NISCH, the coding gene of Nischarin, was predicted as a candidate target of miR-2355-5p in the current study. Previously, NISCH has been implicated in the regulation of cell cycle progression as a tumor suppressor [21][22][23][24]. However, the potential roles of NISCH in HNSC remain unclear.…”

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

“…Implications of involvement in regulation of cell movement and its potential as a druggable receptor made it an interesting target in cancer research. Over the past 20 years nischarin (NISCH) role has been studied mostly in the breast, ovarian [ 3 ] and lung cancer [ 4 , 5 ]. Seminal work on elucidating NISCH role in breast cancer initiation and progression has been done by the Alahari group [ 6 ].…”