• Bulletin of the Korean Chemical Society
• /
• v.35 no.10
• /
• pp.2985-2989
• /
• 2014

Autophagy is a self-digestion process in which intracellular structures are degraded in response to stress. Notably, prolonged autophagy leads to cell death. In this study, we investigated whether CX-4945, an orally available protein kinase 2 (CK2) inhibitor, induces autophagic cell death in human cervical cancer-derived HeLa cells and in human prostate cancer-derived LNCaP cells. CX-4945 treatment of both cell lines resulted in the formation of autophagosomes, in the conversion of microtubule-associated protein 1 light chain 3 (LC3), and in down-regulation of the Akt-mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (S6K) signaling cascade. Thus, pharmacologic inhibition of CK2 by CX-4945 induced autophagic cell death in human cancer cells by down-regulating Akt-mTOR-S6K. These results suggest that autophagy-inducing agents have potential as anti-cancer drugs.

• BMB Reports
• /
• v.47 no.7
• /
• pp.382-387
• /
• 2014

Corn silk (CS) has long been consumed as a traditional herb in Korea. Maysin is a major flavonoid of CS. The effects of maysin on macrophage activation were evaluated, using the murine macrophage RAW 264.7 cells. Maysin was isolated from CS by methanol extraction, and preparative $C_{18}$ reverse phase column chromatography. Maysin was nontoxic up to $100{\mu}g/ml$, and dose-dependently increased TNF-${\alpha}$ secretion and iNOS production by 11.2- and 4.2-fold, respectively, compared to untreated control. The activation and subsequent nuclear translocation of NF-${\kappa}B$ was substantially enhanced upon treatment with maysin ($1-100{\mu}g/ml$). Maysin also stimulated the phosphorylation of Akt and MAPKs (ERK, JNK). These results indicated that maysin activates macrophages to secrete TNF-${\alpha}$ and induce iNOS expression, via the activation of the Akt, NF-${\kappa}B$ and MAPKs signaling pathways. These results suggest for the first time that maysin can be a new immunomodulator, enhancing the early innate immunity.

• Journal of Ginseng Research
• /
• v.48 no.1
• /
• pp.12-19
• /
• 2024

Skeletal muscle (SM) is the largest organ of the body and is largely responsible for the metabolism required to maintain body functions. Furthermore, the maintenance of SM is dependent on the activation of muscle satellite (stem) cells (MSCs) and the subsequent proliferation and fusion of differentiating myoblasts into mature myofibers (myogenesis). Natural compounds are being used as therapeutic options to promote SM regeneration during aging, muscle atrophy, sarcopenia, cachexia, or obesity. In particular, ginseng-derived compounds have been utilized in these contexts, though ginsenoside Rg1 is mostly used for SM mass management. These compounds primarily function by activating the Akt/mTOR signaling pathway, upregulating myogenin and MyoD to induce muscle hypertrophy, downregulating atrophic factors (atrogin1, muscle ring-finger protein-1, myostatin, and mitochondrial reactive oxygen species production), and suppressing the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cachexia. Ginsenoside compounds are also used for obesity management, and their anti-obesity effects are attributed to peroxisome proliferator activated receptor gamma (PPARγ) inhibition, AMPK activation, glucose transporter type 4 (GLUT4) translocation, and increased phosphorylations of insulin resistance (IR), insulin receptor substrate-1 (IRS-1), and Akt. This review was undertaken to provide an overview of the use of ginseng-related compounds for the management of SM-related disorders.

• Journal of Microbiology and Biotechnology
• /
• v.34 no.2
• /
• pp.240-248
• /
• 2024

In cancer treatment, multi-target approach has paid attention to a reasonable strategy for the potential agents. We investigated whether (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) could exert an anticancer effect by dual-regulating VEGFR2 and PPARγ. MMPP showed modulating effects in TNBC type (MDA-MB-231 and MDA-MB-468) and luminal A type (MCF7) breast cancer cell lines. MMPP enhanced PPARγ transcriptional activity and inhibited VEGFR2 phosphorylation. MMPP-induced signaling by VEGFR2 and PPARγ ultimately triggered the downregulation of AKT activity. MMPP exhibited anticancer effects, as evidenced by growth inhibition, inducement of apoptosis, and suppression of migration and invasion. At the molecular level, MMPP activated pro-apoptotic proteins (caspase3, caspase8, caspase9, and bax), while inhibiting the anti-apoptotic proteins (bcl2). Additionally, MMPP inhibited the mRNA expressions of EMT-promoting transcription factors. Therefore, our findings showed molecular mechanisms of MMPP by regulating VEGFR2 and PPARγ, and suggested that MMPP has potential to treat breast cancer.

• Journal of Microbiology and Biotechnology
• /
• v.34 no.7
• /
• pp.1410-1418
• /
• 2024

Alveolar echinococcosis (AE) is a persistent parasite condition that causes the formation of tumorlike growths. It is a challenge to treat the disease. These growths need neovascularization to get their oxygen and nutrients, and the disease is prolonged and severe. Considerable research has been conducted on exosomes and their interactions with Echinococcus multilocularis in the context of immunological evasion by the host. However, the extent of their involvement in angiogenesis needs to be conducted. The primary objective of this investigation was to preliminarily explore the effect of exosomes produced from E. multilocularis protoscoleces (PSC-exo) on angiogenesis, to elucidate the mechanism of their roles in the regulation of the downstream pathway of VEGFA activation, and to provide ideas for the development of novel treatments for AE. The study evaluated the impact of PSC-exo increases proliferation, migration, invasion, and tube formation of HUVECs at concentrations of up to 50 ㎍/ml. In addition, the study sought to validate the findings in vivo. This effect involved increased VEGFA expression at gene and protein levels and AKT/mTOR pathway activation. PSC-exo are crucial in promoting angiogenesis through VEGFA upregulation and AKT/mTOR signaling. This research contributes to our knowledge of neovascularization in AE.

• BMB Reports
• /
• v.45 no.10
• /
• pp.583-588
• /
• 2012

Leukotactin(Lkn)-1 is a CC chemokine and is upregulated in macrophages in response to Mycobacterium tuberculosis (MTB) infection. We investigated whether mitogen-activated protein kinases (MAPKs) are involved in MTB-induced expression of Lkn-1. The up-regulation of Lkn-1 by infection with MTB was inhibited in cells treated with inhibitors specific for JNK (SP600125) or p38 MAPK (SB202190). Since the up-regulation of Lkn-1 by MTB has been reported to be mediated by the PI3-K/PDK1/Akt signaling, we examined whether JNK and/or p38 MAPK are also involved in this signal pathway. MTB-induced Akt phosphorylation was blocked by treatment with JNK- or p38 MAPK-specific inhibitors implying that p38 and JNK are upstream of Akt. In addition, treatment with the PI3-K-specific inhibitor inhibited MTB-stimulated activation of JNK or p38 MAPK implying that PI3-K is upstream of JNK and p38 MAPK. These results collectively suggest that JNK and p38 MAPK are involved in the signal pathway responsible for MTB-induced up-regulation of Lkn-1.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.8
• /
• pp.3363-3368
• /
• 2014

Background: Curcumin, a phenolic compound extracted from the rhizomes of Curcuma longa, has shown cytotoxic effects against a variety of cancers. The aim of this study was to identify potential microRNA (miRNA) mediators of the anticancer effects of curcumin in ovarian cancer cells. Materials and Methods: SKOV3 ovarian cancer cells were treated with curcumin ($10-60{\mu}M$) and miR-9 expression, cell proliferation, and apoptosis were assessed. The effects of miR-9 depletion on curcumin-mediated growth suppression were also examined. Phosphorylation of Akt and forkhead box protein O1 (FOXO1) was measured in cells with miR-9 overexpression or curcumin treatment. Results: Curcumin caused a significant and dose-dependent increase of miR-9 expression in SKOV3 cells, while significantly impeding cell proliferation and stimulating apoptosis. Depletion of miR-9 significantly (p<0.05) attenuated the growth-suppressive effects of curcumin on SKOV3 cells, coupled with reduced percentages of apoptotic cells. In contrast, overexpression of miR-9 significantly enhanced the cleavage of caspase-3 and poly(ADP-ribose) polymerase and promoted apoptotic death in SKOV3 cells. Western blot analysis showed that both miR-9 overexpression and curcumin similarly caused a significant (p<0.05) decline in the phosphorylation of Akt and FOXO1, compared to untreated cells. Conclusions: The present study provided evidence that curcumin exerts its cytotoxic effects against SKOV3 ovarian cancer cells largely through upregulation of miR-9 and subsequent modulation of Akt/FOXO1 axis. Further studies are needed to identify direct targets of miR-9 that mediate the anticancer effects of curcumin in ovarian cancer cells.

• BMB Reports
• /
• v.44 no.3
• /
• pp.205-210
• /
• 2011

Insulin has antiapoptotic activity in various cell types. However, the signaling pathways underlying the antiapoptotic activity of insulin is not yet known. This study was conducted to determine if cAMP affects the antiapoptotic activity of insulin and the activity of PI3K and ERK in CHO cells expressing human insulin receptors (CHO-IR). Insulin-stimulated ERK activity was completely suppressed by cAMP-elevating agents like as pertussis toxin (Ptx) and cholera toxin (Ctx) after 4 h treatment. Insulin-stimulated PKB/Akt activity was not affected at all. Ptx treatment together with insulin increased the number of apoptotic cells and the degree of DNA fragmentation. Ctx or 8-br-cAMP treatment also increased the number of apoptotic cells and stimulated the cleavage of caspase-3 and the hydrolysis of PARP. Taken together, cAMP antagonizes the antiapoptotic activity of insulin and the main target molecule of cAMP in this process is likely ERK, not PI3K-dependent PKB/Akt.

• Herbal Formula Science
• /
• v.28 no.1
• /
• pp.29-39
• /
• 2020

Objectives : Glucoraphanin is one of the well-known natural glucosinolates found in cruciferous plants. In the present study, we investigated the effects and molecular mechanism of glucoraphanin in dexamethasone-induced skeletal muscle atrophy in vitro model. Methods : The cytotoxic effects of glucoraphanin on C2C12 myoblasts or myotubes were evaluated by MTT assay. The glucoraphanin was evaluated effects in dexamethasone-induced skeletal muscle atrophy in C2C12 myotubes using a real-time PCR, western blots analysis, and immunofluorescence staining of myosin heavy chain. Result : Glucoraphanin had no cytotoxicity on both C2C12 myoblasts or myotubes. Dexamethasone markedly induced muscle atrophy by up-regulating muscle-specific ubiquitin E3 ligase markers, atrogin-1 and MuRF1, and down-regulating MyoD, a myogenic regulatory factor whereas co-treatment of glucoraphanin and dexamethasone dose-dependently inhibited it. Furthermore, decreased expressions of p-Akt, p-FOXO1, and p-FOXO3a induced by dexamethasone were reversed by co-treatment with glucoraphanin and dexamethasone. In addition, dexamethasone obviously reduced myotube diameters, while co-treatment of glucoraphanin and dexamethasone increased those to a similar level as control. Conclusions : These results show that glucoraphanin suppresses dexamethasone-induced muscle atrophy in C2C12 myotubes through activation of Akt/FOXO signaling pathway.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.9
• /
• pp.5017-5021
• /
• 2013

Objective: MicroRNAs (miRNAs) are a small class of non-coding, single-stranded RNAs with a critical role in genesis and maintenance of renal cancer mainly through binding to 3'-untranslated regions (3'UTR) of target mRNAs, which causes a block of translation and/or mRNA degradation. The aim of the present study was to investigate the potential effects of miR-122 in human renal cell carcinomas. Methods: The expression level of miR-122 was quantified by qRT-PCR. MTT, colony formation, invasion and migration assays were used to explore the potential functions of miR-122 in human renal cell carcinoma cells. Results: Cellular growth, invasion and migration in two A498 and 786-O cells were significantly increased after miR-122 transfection. Further experiments demonstrated that overexpression of miR-122 resulted in the increase of phospho-Akt (Ser473) and phospho-mTOR (Ser2448), then activation of mTOR targets, p70S6K and 4E-BP1. Conclusions: The up-regulation of miR-122 may play an important role in the progress of renal cancer through activating PI3K/Akt signal pathway and could be a potential molecular target for anti-cancer therapeutics.