Abstract
BackgroundWaixenicin 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.MethodsWe 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.ResultsIncreased 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).ConclusionsThrough 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.
Highlights
Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be antineoplastic
While Transient receptor potential melastatin 7 (TRPM7) protein expression was weak in the SV40-immortalized human bronchial epithelial 16-HBE cell line, TRPM7 was moderately expressed in SPCA-1 and NCI-H520, and strongly expressed in the SK-MES-1, A549 and 95D human lung cancer cell lines (Fig. 1c)
TRPM7 is an independent indicator of poor prognosis in lung cancer For a functional characterization of TRPM7 in lung cancer, we accessed and analyzed TRPM7 gene expression profile in early stage NSCLC dataset with the series accession number GSE19188 and consisting of large-cell carcinoma (LCC, n = 19), adenocarcinoma (ADC, n = 45), squamous cell cancer (SCC, n = 27) and normal lung tissue (n = 65) were accessed via the Gene Expression Omnibus (GEO) browser
Summary
Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be antineoplastic. The lung CSCs model suggest that the malignant phenotype of lung cancer cells is sustained by a sub-population of cells with enhanced capacity for self-renewal, differentiation and intrinsic resistance to contemporary chemotherapy and radiation These CSCs are increasingly implicated in disease recurrence after definitive therapy and functionally associated with minimal residual disease [4, 5], especially as it has been suggested that conventional chemotherapeutic strategies mainly target proliferating cells, while the CSCs remain untouched by manipulating the multidrug resistant mechanisms, thereby facilitating the relapse of cancer [6]. The delivery or administration of drugs that target and eliminate CSCs may constitute a more efficient therapeutic strategy in the treatment of patients with recurrent or advanced stage lung cancer [7, 8]. Drugs that selectively target CSCs offer a greater promise for cancer therapy and prevention
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