Inotilone from Inonotus linteus suppresses lung cancer metastasis in vitro and in vivo through ROS-mediated PI3K/AKT/MAPK signaling pathways

Abstract

Metastasis is one of the main causes of mortality in cancer patients. Inotilone, a major component of Inonotus linteus, is a traditional Chinese medical herb. In this study, MTT results showed that inotilone had no obvious cytotoxicity. Animal model results revealed that inotilone suppressed cancer metastatic efficacy. Serum results showed that inotilone reduced the activity of matrix metalloproteinase (MMP)-2 and -9 and tumor necrosis factor alpha (TNF-α) activity as well as NO content. Additionally, inotilone affected MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-2 protein expression and improved the activity of the antioxidant enzymes in the lung tissues of LLC-bearing mice. In addition, cell experimental results showed that inotilone reduced the activity of MMP-2/-9 and inhibited the ability for cellular migration and invasion. Inotilone decreased interleukin (IL)-8 expression in A549 cells. Western blot results revealed that inotilone affected the protein expression of MMPs, nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, anti-oxidant enzymes, mitogen activated protein kinase (MAPK), focal adhesion kinase (FAK), phosphoinositide-3 kinase (PI3K)-AKT, and nuclear factor (NF)κB. Therefore, we propose that inotilone is a potential therapeutic candidate against metastatic lung cancer cells.

Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells

“…Interestingly, PMA-induced MVP release was also significantly blocked by PD and SB compounds ( Figure 6 ). These findings are not entirely surprising given that the PMA-induced phospholipase C (PLC) activation interacts with the phosphoinositide 3-kinase (PI3K) pathway, which indicates the crosstalk of the MAPK signaling with both PI3K and PAFR pathways [ 49 , 50 ]. The schematic representation of our working model is shown in Figure 7 .…”

YARS as an oncogenic protein that promotes gastric cancer progression through activating PI3K-Akt signaling

“…In contrast to bacterial or low-eukaryotic homologs, higheukaryotic YARS (including human) specifically contains a C-terminal domain and can be split by proteolysis into two distinct cytokine mimics: an IL-8 (interleukin 8)-like N-domain derivative and an EMAP II (endothelial-monocyte-activating polypeptide II)-like C-domain derivative (Wakasugi and Schimmel 1999). IL-8 causes the recruitment of inflammatory cells and is also implicated in mediating cancerous progression (Chao et al 2019). By acting on the CXCR1/2 receptor, the IL-8-like fragment (aka "mini-YARS") induces cell migration as a monomer or inhibits migration as a dimer (Vo et al 2011); mini-YARS was also reported potentially leading to angiogenesis by activating VEGFR2 or VEGF (Tzima et al 2005;Zeng et al 2014).…”

Focal Adhesion Kinase Inhibitor Inhibits the Oxidative Damage Induced by Central Venous Catheter via Abolishing Focal Adhesion Kinase-Protein Kinase B Pathway Activation

“…When noxious stimuli act on cells, phosphorylated FAK or part of FAK-related signaling pathways can upregulate intracellular ROS levels, leading to abnormal cellular oxidative metabolism [ 28 , 29 ]. Y15, an FAK inhibitor, can target the Y397 site of FAK and inhibits its autophosphorylation [ 21 ], thereby regulating NO, ROS, MDA, and SOD levels [ 30 , 31 ] via inhibiting of Src/FAK, PI3K/Akt/endothelial nitric oxide synthase (eNOS), and FAK/Akt/eNOS signaling pathways [ 19 , 20 ] and resulting in reduced oxidative stress [ 32 ]. In addition, inhibiting FAK activation is also beneficial to alleviate the inflammatory damage [ 33 ].…”

“…Additionally, ROS and cytokines that cause endothelial dysfunction can induce FAK family activation [ 17 , 18 ]. Thus, the inhibition of both phosphorylation of FAK and protein kinase B (AKT) should play an important role in antioxidation, anti-inflammation, and tumor microenvironment improvement [ 19 ]. Inhibition of Akt (Thr308 and Ser473) phosphorylation through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway significantly reduces acute lung injury [ 20 ].…”