Sinulariolide Suppresses Cell Migration and Invasion by Inhibiting Matrix Metalloproteinase-2/-9 and Urokinase through the PI3K/AKT/mTOR Signaling Pathway in Human Bladder Cancer Cells

Abstract

Sinulariolide is a natural product extracted from the cultured-type soft coral Sinularia flexibilis, and possesses bioactivity against the movement of several types of cancer cells. However, the molecular pathway behind its effects on human bladder cancer remain poorly understood. Using a human bladder cancer cell line as an in vitro model, this study investigated the underlying mechanism of sinulariolide against cell migration/invasion in TSGH-8301 cells. We found that sinulariolide inhibited TSGH-8301 cell migration/invasion, and the effect was concentration-dependent. Furthermore, the protein expressions of matrix metalloproteinases (MMPs) MMP-2 and MMP-9, as well as urokinase, were significantly decreased after 24-h sinulariolide treatment. Meanwhile, the increased expression of tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 were in parallel with an increased concentration of sinulariolide. Finally, the expressions of several key phosphorylated proteins in the mTOR signaling pathway were also downregulated by sinulariolide treatment. Our results demonstrated that sinulariolide has significant effects against TSGH-8301 cell migration/invasion, and its effects were associated with decreased levels of MMP-2/-9 and urokinase expression, as well as increased TIMP-1/TIMP-2 expression. The inhibitory effects were mediated by reducing phosphorylation proteins of the PI3K, AKT, and mTOR signaling pathway. The findings suggested that sinulariolide is a good candidate for advanced investigation with the aim of developing a new drug for the treatment of human bladder cancer.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…AKT inhibits the cell cycle blockade by phosphorylating P27kip1 and accelerates cell proliferation and differentiation [105]. Additionally, mTOR helps to regulate the synthesis of biological macromolecules such as proteins, nucleotides, and lipids, thus providing the materials necessary for cancer cell growth [106].…”

“…There are 23 types of MMPs, and MMP-2 and MMP-9 are known to be crucial for cell invasion. PI3K/AKT/mTOR can promote the expression of MMP-2 at the mRNA and protein levels, degrade the extracellular matrix, and promote the invasion and metastasis of cancer cells [106].…”

lncRNA DLEU1 contributes to tumorigenesis and development of endometrial carcinoma by targeting mTOR

“…A large number of articles have confirmed that PI3K/AKT/mTOR pathway plays an important role in the tumor, and its targeted inhibition has become a hot topic in drug research. [24][25][26][27][28][29] In endometrial carcinoma, the role of PI3K/AKT/ mTOR pathway has been extensively studied. This pathway is associated with the promotion of tumor properties, poor prognosis, and traditional drug resistance, and targeted inhibition of PI3K/AKT/ mTOR pathway in the treatment of endometrial carcinoma has shown excellent results, in both preclinical and clinical trials.…”

Sinulariolide Inhibits Gastric Cancer Cell Migration and Invasion through Downregulation of the EMT Process and Suppression of FAK/PI3K/AKT/mTOR and MAPKs Signaling Pathways

“…Furthermore, cytotoxicity is one of the main characteristics of such compounds [9][10][11]. Many researchers have reported that compounds isolated from marine soft corals, such as diterpenoids, diterpenes, and prostanoids, have an effect on apoptosis in several types of cancer cells, including melanoma, oral squamous cell carcinoma, bladder, breast, cervical, colon, and liver cancer cells [12][13][14][15][16][17][18]. Sinulariolide is an active compound extracted from cultured soft coral Sinularia flexibilis.…”