TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90α/uPA/MMP2 signaling pathway

• Published in: BMC cancer Vol. 18; no. 1; pp. 1167 - 12
• Main Authors: Liu, Kai, Xu, Shao-Hua, Chen, Zhao, Zeng, Qing-Xin, Li, Zhi-Jun, Chen, Zhou-Miao
• Format: Journal Article
• Language: English
• Published: England BioMed Central 26.11.2018; BMC
• Subjects: Apoptosis; Breast cancer; cancer stem cells; Cancer therapies; Cell cycle; Cell Line, Tumor; Chemotherapy; Fatalities; Gelatinase A; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins - metabolism; Humans; Immunohistochemistry; Kinases; KLF4 protein; Lung Cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Lymph nodes; Matrix Metalloproteinase 2 - metabolism; Medical prognosis; Mesenchyme; Metastases; Metastasis; Motility; Neoplasm Metastasis; Neoplasm Staging; Neoplastic Stem Cells - metabolism; Phenotype; Phenotypes; Phytochemicals; Prognosis; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Signal Transduction; Stem cells; Transient receptor potential proteins; TRPM Cation Channels - antagonists & inhibitors; TRPM Cation Channels - genetics; TRPM7; Waixenicin A; TRPM7; Lung Cancer; cancer stem cells; Waixenicin A
• DOI: 10.1186/s12885-018-5050-x
• ISSN: 1471-2407

Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be anti-neoplastic. However, its mechanisms of action remain unclear. Cancer stem cells (CSCs) and associated stemness factors are implicated in lung cancer. Here, we investigated the role of Waixenicin A on CSCs-like and metastatic lung cancer cells. We demonstrated and compared TRPM7 expression in the non-tumor lung tissues or bronchial epithelial 16-HBE cell line. TRPM7 was aberrantly expressed in the cancer tissues and SPCA-1, NCI-H520, SK-MES-1, A549 and 95D cell lines. Increased TRPM7 expression was associated with enhanced SOX2, KLF4, and CD133, Hsp90α, uPA, and MMP2 expression in lung cancer cells. TRPM7-silencing inhibited epithelial-to-mesenchymal transition (EMT), suppressed stemness markers and phenotypes, concomitantly suppressed Hsp90α/uPA/MMP2 axis. Coincidently, Waixenicin A treatment downregulated TRPM7 and oncogenic markers; Waixenicin A also attenuated the ability of lung cancer cells to form tumorspheres, in vitro. In validation, our clinicopathological analyses showed that a higher TRPM7 expression was positively correlated with the larger tumor size (p = 0.007), positive lymph node metastasis (p = 0.005) and disease grade (p = 0.003). Through its ability to inhibit Hsp90α/uPA/MMP2 signaling and suppress TRPM7 expression, we showed that Waixenicin A is a potential anticancer therapeutic agent for treating malignant lung cancer.