S100P, a Ca2+ binding protein, has been shown to be overexpressed in various cancers. However, its functional character in lung cancer remains largely unknown. In this study, we show that S100P increases cancer migration, invasion and metastasis in lung cancer cells. Ectopic expression of S100P increases migration, invasion and EMT in less invasive CL1-0 lung cancer cells. Conversely, knockdown of S100P suppressed migration and invasion, and caused a reversion of EMT in highly invasive lung cancer cells. These effects were transduced by increasing the interaction of S100P with integrin α7, which activated focal adhesion kinase (FAK) and AKT. Blocking FAK significantly decreased S100P-induced migration by decreasing Src and AKT activation, whereas inhibiting AKT reduced S100P upregulation on ZEB1 expression. Further study has indicated that S100P knockdown prevents the spread of highly metastatic human lung cancer in animal models. This study therefore suggests that S100P represents a critical activator of lung cancer metastasis. Detection and targeted treatment of S100P-expressing cancer is an attractive therapeutic strategy in treating lung cancer.
Lung cancer accounts for 12% of all new cases of cancers worldwide and is the leading cause of cancer-related death. S100P, a calcium binding protein, has been reported to involve in cancer metastasis. However, the role of S100P is poorly known in lung cancer. This study first reports that S100P enhances the migration and invasion ability of lung cancer cells through the Twist1 upregulation and FAK (focal adhesion kinase)/Src/AKT signaling pathway. Compared to low invasive CL1-0, the expression of S100P is greater in that of high invasive CL1-5 cells. Overexpression of S100P increases the migration and invasion in CL1-0 cells, whereas knockdown of S100P expression decreases the migration and invasion of CL1-5 cells. Enhancement of S100P expression triggers FAK activation, which in turn increases the activation of Src and AKT signaling. Blockade of FAK by specific inhibitor prevents S100P-mediated cell migration and invasion. In the other hand, S100P also increases Twist1, which is responsible for epithelial-mesenchymal transition in lung cancer. More important, elevated expression of S100P protein was also found in human lung cancer specimen. This study demonstrates that S100P may be a novel anticancer target gene for the prevention of non-small cell lung cancer metastasis. In other way, it also can be a biomarker for prognosis of lung cancer metastasis. Citation Format: Yung-Yu Liang, Po-Lin Kuo, Ya-Ling Hsu. S100P increases Twist expression and triggers FAK/AKT signaling in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5265. doi:10.1158/1538-7445.AM2014-5265
Introduction: More than 25% of patients diagnosed with endometrial carcinoma have an invasive primary cancer accompanied by metastasis. The kisspeptin has an important role in reproduction. In mammals, kisspeptin may regulate tumor progression of endometrial cancer. FAK and Src signaling have been considered important components of tumor progression. MMPs are largely implicated in promoting angiogenesis and tumor metastasis. In the present study, we examined the action of kisspeptin-promoted motility of endometrial cancer cells and the mechanisms of the action in endometrial cancer. Materials and methods: Endometrial cancer cell line Ishikawa and ECC-1 were derived from an endometrial adenocarcinoma. Kisspeptin agonist and antagonist were synthetic peptides. Cell motility was estimated by invasion and migration assay. The activities of MMP-2 was assessed by gelatin zymography. Immunoblot analysis was done to study the expression of kisspeptin receptor and the effects of kisspeptin in the activation of FAK,Src and MMP-2. Human FAK siRNA and Src siRNA were used to knock down the expression of FAK and Src to evaluate the effects of FAK and Src. MMP-2 inhibitor (OA-Hy) was pretreated for 30 min to evaluate the effects of MMP-2 in cell motility. Results: The kisspeptin regulated cell motility in a dose-dependent manner. Kisspeptin activated the phosphorylation of FAK and Src signaling and the phosphorylation was abolished by FAK siRNA and Src siRNA. Kisspeptin-regulated cell motility was suppressed in cells pretreated with FAK siRNA and Src siRNA. Moreover, FAK siRNA and Src siRNA abolished kisspeptin-induced activation of MMP-2. Inhibition of MMP-2 with 10μM OA-Hy suppressed cell motility in response to kisspeptin. Conclusion: Our study shows that the kisspeptin regulated the cell motility of endometrial cancer cells through the kisspeptin receptor, and the phosphorylation of FAK and Src-dependent activation of MMP-2. Our findings represent a new concept regarding the mechanisms of kisspeptin-regulated cell motility in endometrial cancer cells, suggesting the possibility of kisspeptin analogues as a potential therapeutic intervention for the treatment of human endometrial cancer. Citation Format: Hsien-Ming Wu, Yung-Yu Liang, Wei-Jung Chiu, Hsin-Shih Wang, Hong-Yuan Huang, Chyong-Huey Lai, Yung-Kuei Soong. Kisspeptin regulates the invasiveness of endometrial cancer cells through FAK/ Src signaling-dependent activation of matrix metalloproteinase (MMP)-2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3481.
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