Flaccidoxide-13-Acetate Extracted from the Soft Coral Cladiella kashmani Reduces Human Bladder Cancer Cell Migration and Invasion through Reducing Activation of the FAK/PI3K/AKT/mTOR Signaling Pathway.

Choo-Aun Neoh,Chih-I Liu,Tzu-Rong Su,Wen-Tung Wu,Guo-Fong Dai,Yu-Jen Wu,Jui-Hsin Su

doi:10.3390/molecules23010058

Abstract

Metastasis of cancer is the cause of the majority of cancer deaths. Active compound flaccidoxide-13-acetate, isolated from the soft coral Cladiella kashmani, has been found to exhibit anti-tumor activity. In this study, Boyden chamber analysis, Western blotting and gelatin zymography assays indicated that flaccidoxide-13-acetate exerted inhibitory effects on the migration and invasion of RT4 and T24 human bladder cancer cells. The results demonstrated that flaccidoxide-13-acetate, in a concentration-dependent manner, reduced the levels of matrix metalloproteinase-2 (MMP-2), MMP-9, urokinase-type plasminogen activator receptor (uPAR), focal adhesion kinase (FAK), phosphatidylinositide-3 kinases (PI3K), p-PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, Ras homolog gene family, member A (Rho A), Ras, mitogen-activated protein kinase kinase 7 (MKK7) and mitogen-activated protein kinase kinase kinase 3 (MEKK3), and increased the expressions of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in RT4 and T24 cells. This study revealed that flaccidoxide-13-acetate suppressed cell migration and invasion by reducing the expressions of MMP-2 and MMP-9, regulated by the FAK/PI3K/AKT/mTOR pathway. In conclusion, our study was the first to demonstrate that flaccidoxide-13-acetate could be a potent medical agent for use in controlling the migration and invasion of bladder cancer.

Highlights

Urothelial carcinoma, called transitional cell carcinoma (TCC), is a malignant tumor arising from the transitional epithelium of the urinary tract [1]
The results of cell migration and invasion experiments demonstrated that the expressions and enzyme activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase (MMP)-9 decreased with an increasing flaccidoxide-13-acetate concentration in both T24 and RT4 cells, while the expression levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and Tissue inhibitors of metalloproteinases (TIMPs)-2 increased with an increasing flaccidoxide-13-acetate concentration
Our results demonstrated that the specific phosphatidylinositide-3 kinases (PI3K) inhibitor, LY294002, significantly suppressed the cell migration, and markedly inhibited the MMP-2 and MMP-9 proteins expression (Figure 6)

Summary

Introduction

Urothelial carcinoma, called transitional cell carcinoma (TCC), is a malignant tumor arising from the transitional epithelium of the urinary tract [1]. Treatment becomes more challenging when tumor metastasis occurs, and systemic therapy in the main, such as immune therapy or chemotherapy, is used to control the growth of metastatic cancer cells [9]. A combination of chemotherapy and radiation for the treatment of invasive bladder cancer in patients who are not candidates for or decline cystectomy has been developed [12,13]. Metastasis is responsible for the majority of cancer deaths, and whether or not metastasis occurs or not is often seen as an index of treatment efficiency and disease severity in the care of cancer patients. Understanding the details of the molecular mechanism will assist in the development new drugs against cancer [14]

Methods

Results

Conclusion