Timosaponin AIII inhibits migration and invasion of A549 human non-small-cell lung cancer cells via attenuations of MMP-2 and MMP-9 by inhibitions of ERK1/2, Src/FAK and ß-catenin signaling pathways.

Timosaponin AIII (TAIII) is a type of steroidal saponins isolated from Anemarrhena asphodeloides. It was known to improve learning and memory deficits through anti-inflammatory effects. TAIII was also reported to induce autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells and inhibit the growth of human colorectal cancer cells, thus regarded as a potential candidate for anti-cancer agent. In this study, we verified apoptosis-inducing and cell-cycle-arresting effects of TAIII in A549 human non-small-cell lung cancer (NSCLC) cells. Then, we report that TAIII suppresses migration and invasion of A549 human NSCLC cells. We propose that two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, which are well known to be involved in cancer-metastasis, are attenuated by the treatment of TAIII. TAIII exerts its suppressive effects on MMP-2 and MMP-9 via inhibitions of ERK1/2, Src/FAK and ß-catenin signalings which are closely related with the regulations of MMP-2 and MMP-9.

MARS2 drives metabolic switch of non-small-cell lung cancer cells via interaction with MCU.

Mitochondrial methionyl-tRNA synthetase (MARS2) canonically mediates the formation of fMet-tRNAifMet for mitochondrial translation initiation. Mitochondrial calcium uniporter (MCU) is a major gate of Ca2+ flux from cytosol into the mitochondrial matrix. We found that MARS2 interacts with MCU and stimulates mitochondrial Ca2+ influx. Methionine binding to MARS2 would act as a molecular switch that regulates MARS2-MCU interaction. Endogenous knockdown of MARS2 attenuates mitochondrial Ca2+ influx and induces p53 upregulation through the Ca2+-dependent CaMKII/CREB signaling. Subsequently, metabolic rewiring from glycolysis into pentose phosphate pathway is triggered and cellular reactive oxygen species level decreases. This metabolic switch induces inhibition of epithelial-mesenchymal transition (EMT) via cellular redox regulation. Expression of MARS2 is regulated by ZEB1 transcription factor in response to Wnt signaling. Our results suggest the mechanisms of mitochondrial Ca2+ uptake and metabolic control of cancer that are exerted by the key factors of the mitochondrial translational machinery and Ca2+ homeostasis.

Synergistic anticancer effects of timosaponin AIII and ginsenosides in MG63 human osteosarcoma cells.

BACKGROUND: Timosaponin AIII (TA3) is a steroidal saponin extracted from Anemarrhena asphodeloides. Here, we investigated the anticancer effects of TA3 in MG63 human osteosarcoma cells. TA3 attenuates migration and invasion of MG63 cells via regulations of two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, which are involved with cancer metastasis in various cancer cells. TA3 reduced enzymatic activities and transcriptional expressions of MMP-2 and MMP-9 in MG63 cells. TA3 also inhibited Src, focal adhesion kinase, extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, ß-catenin, and cAMP response element binding signaling, which regulate migration and invasion of cells. TA3 induced apoptosis of MG63 cells via regulations of caspase-3, caspase-7, and poly(ADP-ribose) polymerase (PARP). Then, we tested several ginsenosides to be used in combination with TA3 for the synergistic anticancer effects. We found that ginsenosides Rb1 and Rc have synergistic effects on TA3-induced apoptosis in MG63 cells. METHODS: We investigated the anticancer effects of TA3 and synergistic effects of various ginseng saponins on TA3-induced apoptosis in MG63 cells. To test antimetastatic effects, we performed wound healing migration assay, Boyden chamber invasion assays, gelatin zymography assay, and Western blot analysis. Annexin V/PI staining apoptosis assay was performed to determine the apoptotic effect of TA3 and ginsenosides. RESULTS: TA3 attenuated migration and invasion of MG63 cells and induced apoptosis of MG63 cells. Ginsenosides Rb1 and Rc showed the synergistic effects on TA3-induced apoptosis in MG63 cells. CONCLUSIONS: The results strongly suggest that the combination of TA3 and the two ginsenosides Rb1 and Rc may be a strong candidate for the effective antiosteosarcoma agent.

Maclurin exerts anti-cancer effects on PC3 human prostate cancer cells via activation of p38 and inhibitions of JNK, FAK, AKT, and c-Myc signaling pathways.

Maclurin is a phenolic compound extracted from purple mangosteen and mulberry twigs. Earlier reports indicated that it exerts antioxidant activity. We hypothesized that maclurin exerts antioxidant activity and anti-cancer effects in small cell neuroendocrine carcinomas (SCNCs), a very aggressive type of human prostate cancer. To verify our hypothesis, we selected PC3 cells as a model system and investigated the antioxidant activity and anti-cancer effects of maclurin. In the reactive oxygen species (ROS) detection assay for the verification of antioxidant activity, we observed the unexpected prooxidant activity of maclurin in PC3 cells. For the anti-cancer activities, we investigated the effects of maclurin on induction of apoptosis and inhibition of metastatic characteristics of PC3 cells. In the apoptosis assay, maclurin significantly induced apoptosis of PC3 cells. Maclurin also showed significant anti-metastatic effects. Maclurin inhibited cell migration in a dosage-dependent manner. In addition, the gelatin zymography assay indicated that maclurin inhibited activities of matrix metalloproteinase-2 and 9 (MMP-2 and MMP-9) that affect cell migration and extracellular matrix (ECM) degradation. Then, we investigated the effects of maclurin on the cancer-related signaling molecules. Maclurin activated p38 signaling and inhibited c-Jun N-terminal kinase (JNK), focal-adhesion kinase (FAK), AKT, and c-Myc signalings in PC3 cells. Finally, we observed prooxidant activity and anti-SCNC effects of maclurin in DU145 cells. This suggests that the effects of maclurin may not be specifically limited to PC3 cells. Our findings suggest that maclurin exerts anti-cancer effects on SCNC cells via activation of p38 and inhibitions of JNK, FAK, AKT and c-Myc signalings.

Emetine inhibits migration and invasion of human non-small-cell lung cancer cells via regulation of ERK and p38 signaling pathways.

Emetine is a natural compound originated from ipecac roots. It was commonly used as anti-protozoal and vomiting agent. The apoptosis-inducing effect of emetine makes it considered as a potential anti-cancer agent for various human cancers. Here in this study, we report that emetine inhibits migration and invasion of human non-small-cell lung cancer (NSCLC) cells. Modulation of three major mitogen-activated protein kinases (MAPKs), ERK, p38 and JNK, is well known to be involved in regulation of matrix metalloproteinases (MMPs), which are essential in tissue remodeling and extracellular matrix (ECM) degradation, for cancer cells to spread out from the origin of tumorigenesis. Emetine regulates two major MAPKs, p38 and ERK. Differential inhibition/stimulation of ERK and p38 induced differential suppressions of ß-catenin and c-myc transcription factors. This leads to the selective down-regulation of MMP-2 and MMP-9, two major gelatinases which can degrade ECM components, and RECK, a negative regulator of MMP-9.