Silicon dioxide nanoparticles induce COX-2 expression through activation of STAT3 signaling pathway in HaCaT cells

Kundu, Juthika,Kim, Do-Hee,Chae, In Gyeong,Lee, Jong Kwon,Lee, Sooyeun,Jeong, Chul-Ho,Chun, Kyung-Soo Elsevier 2018 Toxicology in vitro Vol.52 No.-

<P><B>Abstract</B></P> <P>Silicon dioxide nanoparticles (SiO<SUB>2</SUB>-NPs) are widely used in biomedicines and consumer products, such as sunscreens and cosmetics. However, SiO<SUB>2</SUB>-NPs can cause adverse effects on human health, depending on the size and concentration of nanoparticles. The present study was aimed at investigating the molecular mechanism underlying SiO<SUB>2</SUB>-NPs-induced inflammation in human keratinocyte (HaCaT) cells. Incubation of HaCaT cells with SiO<SUB>2</SUB>-NPs induced the expression of cyclooxygenase-2 (COX-2) mRNA and protein. Treatment of cells with SiO<SUB>2</SUB>-NPs also induced the phosphorylation, DNA binding and the reporter gene activity of signal transducer and activator of transcription 3 (STAT3). Transfection of cells with STAT3 siRNA abrogated SiO<SUB>2</SUB>-NPs-induced COX-2 expression. Moreover, SiO<SUB>2</SUB>-NPs enhanced the phosphorylation of Janus kinase2 (JAK2), Src and Akt. Pharmacological inhibition of either JAK2, Src or Akt abrogated SiO<SUB>2</SUB>-NPs-induced STAT3 transcriptional activity and the expression of COX-2. Treatment with LY294002 also attenuated SiO<SUB>2</SUB>-NPs-induced Src phosphorylation, while, JAK2 phosphorylation was not changed. In addition, SiO<SUB>2</SUB>-NPs generated reactive oxygen species (ROS) and treatment of <I>N</I>-acetyl cysteine (NAC) attenuated the phosphorylation of JAK2, Src, Akt and STAT3, as well as the expression of COX-2 in SiO<SUB>2</SUB>-NPs-treated HaCaT cells. Taken together, our study provides the first report that SiO<SUB>2</SUB>-NPs induce COX-2 expression in HaCaT cells by activating the STAT3 signaling through ROS-mediated phosphorylation of upstream kinases, Akt/Src and JAK2.</P> <P><B>Highlights</B></P> <P> <UL> <LI> This study examined the molecular mechanism of SiO2-NPs-induced inflammation in human keratinocyte (HaCaT) cells. </LI> <LI> SiO2-NPs induce the phosphorylation of JAK2, Src and Akt through ROS generation. </LI> <LI> SiO2-NPs induce COX-2 expression in HaCaT cells by activating the STAT3 signaling. </LI> </UL> </P>

SiO₂ nanoparticles induce COX-2 expression through activation of STAT3 signaling in human keratinocyte HaCaT cells

Juthika Kundu(주티카 쿤두),In Gyeong Chae(채인경),Ji-Eun Park(박지은),Kyung-Soo Chun(천경수) 환경독성보건학회 2014 한국독성학회 심포지움 및 학술발표회 Vol.2014 No.5

Fraxetin Induces Heme Oxygenase-1 Expression by Activation of Akt/Nrf2 or AMP-activated Protein Kinase /Nrf2 Pathway in HaCaT Cells

Juthika Kundu,채인경,천경수 대한암예방학회 2016 Journal of cancer prevention Vol.21 No.3

Background: Fraxetin (7,8-dihydroxy-6-methoxy coumarin), a coumarin derivative, has been reported to possess antioxidative, antiinflammatory and neuroprotective effects. A number of recent observations suggest that the induction of heme oxygenase-1 (HO-1) inhibits inflammation and tumorigenesis. In the present study, we determined the effect of fraxetin on HO-1 expression in HaCaT human keratinocytes and investigated its underlying molecular mechanisms. Methods: Reverse transcriptase-PCR and Western blot analysis were performed to detect HO-1 mRNA and protein expression, respectively. Cell viability was measured by the MTS test. The induction of intracellular reactive oxygen species (ROS) by fraxetin was evaluated by 2‘,7‘-dichlorofluorescin diacetate staining. Results: Fraxetin upregulated mRNA and protein expression of HO-1. Incubation with fraxetin induced the localization of nuclear factor-erythroid-2-related factor-2 (Nrf2) in the nucleus and increased the antioxidant response element-reporter gene activity. Fraxetin also induced the phosphorylation of Akt and AMP-activated protein kinase (AMPK)α and diminished the expression of phosphatase and tensin homolog, a negative regulator of Akt. Pharmacological inhibition of Akt and AMPKα abrogated fraxetin-induced expression of HO-1 and nuclear localization of Nrf2. Furthermore, fraxetin generated ROS in a concentration-dependent manner. Conclusions: Fraxetin induces HO-1 expression through activation of Akt/Nrf2 or AMPKα/Nrf2 pathway in HaCaT cells.

Carnosol: A Phenolic Diterpene With Cancer Chemopreventive Potential

전경수,Juthika Kundu,채인경,Kundu, Joydeb Kumar 대한암예방학회 2014 Journal of cancer prevention Vol.19 No.2

Cancer is an unbeaten health challenge for the humankind. After striving for decades to find a cancer cure, attention has now been shifted to reduce the morbidity and mortality from cancer by halting the course of tumor development. Numerous bioactive phytochemicals, especially those present in edible and non-edible plant species, have been reported to reduce the risk of many cancers. Multiple lines of evidence suggest that carnosol, a phenolic diterpene present in rosemary (Rosmarinus officinalis L.), holds the promise of preventing certain types of cancer. A remarkable progress has been made in delineating the biochemical mechanisms underlying the chemopreventive effects of carnosol. Results from in vitro cell culture studies as well as animal model experiments have revealed that carnosol inhibits experimentally induced carcinogenesis and exhibits potent anti-oxidative, anti-inflammatory, antiproliferative and apoptosis inducing properties. Moreover, carnosol enhances the sensitivity of chemoresistant cancer cells to chemotherapeutic agents. The purpose of this review is to shed light on the detailed mechanistic aspects of cancer chemoprevention with carnosol.

Methanol Extract of Flacourtia indica Aerial Parts Induces Apoptosis via Generation of ROS and Activation of Caspases in Human Colon Cancer HCT116 Cells

Park, Ki-Woong,Kundu, Juthika,Chae, In Gyeong,Bachar, Sitesh Chandra,Bae, Jung-Woo,Chun, Kyung-Soo Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.17

Different plant parts of Flacourtia indica have long been used in Ayurvedic medicine. Previous studies have demonstrated that the methanolic extract of F. indica possess anti-inflammatory properties. The present study was aimed at investigating the anticancer effects of methanol extract of Flacourtia indica (FIM) aerial parts in human colon cancer (HCT116) cells. Treatment of cells with FIM at a concentration of $500{\mu}g/ml$ for 24 hours significantly reduced cell viability and induced apoptosis, which was associated with the increased cytoplasmic expression of cytochrome c, activation of caspase-3, and the cleavage of poly-(ADP-ribose) polymerase. Incubation with FIM also inhibited the levels of Bcl-2, Bcl-xl and survivin, which are the markers of cell proliferation, whereas the expression of Bax remained unchanged. Treatment with FIM led to the generation of reactive oxygen species (ROS) in a concentration-dependent manner. Pharmacological inhibition of ROS generation by pretreatment of cells with N-acetyl cysteine abrogated FIM-induced apoptosis in HCT116 cells. Thus, these results demonstrate that FIM has anti-proliferative and pro-apoptotic effects in HCT116 cells and the effects are, at least in part, due to the ROS dependent activation of caspases.

SMAD4 Suppresses AURKA-Induced Metastatic Phenotypes via Degradation of AURKA in a TGFβ-Independent Manner

Jia, Lina,Lee, Hun Seok,Wu, Chun Fu,Kundu, Juthika,Park, Sang Gyu,Kim, Ryong Nam,Wang, Li-Hui,Erkin, Ö,zgü,r Cem,Choi, Jong-Sun,Chae, Seoung Wan,Yang, Ho Bin,Choi, Yoon-La,Shin, Young Kee American Association for Cancer Research 2014 Molecular Cancer Research Vol.12 No.12

<P>SMAD4 has been suggested to inhibit the activity of the WNT/β-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/β-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of β-catenin/T-cell factor (TCF) complex by stabilizing β-catenin through the inhibition of GSK-3β. Here, SMAD4 modulated AURKA in a TGFβ-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function, including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the β-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of β-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and β-catenin was independent of TGFβ signaling because blockage of TGFβR1 or restoration of TGFβ signaling did not prevent suppression of AURKA and β-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by downregulation of β-catenin transcriptional activity via AURKA degradation in a TGFβ-independent manner.</P><P><B>Implications:</B> SMAD4 interacts with AURKA and antagonizes its tumor-promoting potential, thus demonstrating a novel mechanism of tumor suppression. <I>Mol Cancer Res; 12(12); 1779–95. ©2014 AACR</I>.</P>

Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells

PARK, JI EUN,PARK, BYOUNGDUCK,CHAE, IN GYEONG,KIM, DO-HEE,KUNDU, JUTHIKA,KUNDU, JOYDEB KUMAR,CHUN, KYUNG-SOO Spandidos Publications 2016 ONCOLOGY REPORTS Vol.35 No.5

<P>Carnosic acid (CA), the major bioactive compound of Rosmarinus officinalis L., has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. In the present study, we investigated that CA significantly reduced the viability of human renal carcinoma Caki cells. CA-induced apoptosis was connected with the cleavage of caspase-9, -7 and -3, and that of PARP. Moreover, CA increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 and Bcl-xL, thereby releasing cytochrome c into the cytosol. Treatment with CA in Caki cells also induced the expression of p53 and its target gene product, p27, through down-regulation of Murine double minute-2 (Mdm2). Furthermore, CA generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) abrogated CA-induced cleavage of PARP and expression of p53. One of the key oncogenic signals is mediated through signal transducer and activator of transcription-3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with CA markedly diminished the phosphorylation of STAT3 and its upstream, Src, and reduced the expression of STAT3 responsive gene products, such as D-series of cyclins and survivin. Taken together, the present study revealed that CA induced apoptosis in Caki cells by induction of p53 and suppression of STAT3 signaling.</P>