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Kaewpiboon Chutima,Boonnak Nawong,Kaowinn Sirichat,Yawut Natpaphan,Chung Young-Hwa 대한암예방학회 2022 Journal of cancer prevention Vol.27 No.2
Considering that presence of cancer stem cell (CSC) subpopulation in tumor tissues confers anticancer drug resistance, we investigated whether human A549 lung cancer cells resistant to etoposide possess CSC-like phenotypes. Furthermore, it is known that these malignant tumor features are the leading cause of treatment failure in cancer. We have thus attempted to explore new therapeutic agents from natural products targeting these malignancies. We found that formoxanthone C (XanX), a 1,3,5,6-tetraoxygenated xanthone from Cratoxylum formosum ssp. pruniflorum, at a non-cytotoxic concentration reduced the expression of the signal transducer and activator of transcription 1 (STAT1) and histone deacetylase 4 (HDAC4) proteins, leading to inhibition of CSC-like phenotypes such as cell migration, invasion, and sphere-forming ability. Moreover, we found that treatment with STAT1 or HDAC4 small interfering RNAs significantly hindered these CSC-like phenotypes, indicating that STAT1 and HDAC4 play a role in the malignant tumor features. Taken together, our findings suggest that XanX may be a potential new therapeutic agent targeting malignant lung tumors.
Kaewpiboon, Chutima,Boonnak, Nawong,Kaowinn, Sirichat,Chung, Young-Hwa Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.4
<P><B>Abstract</B></P> <P>Multidrug resistance (MDR) cancer toward cancer chemotherapy is one of the obstacles in cancer therapy. Therefore, it is of interested to use formoxanthone C (1,3,5,6-tetraoxygenated xanthone; XanX), a natural compound, which showed cytotoxicity against MDR human A549 lung cancer (A549RT-eto). The treatment with XanX induced not only apoptosis- in A549RT-eto cells, but also autophagy-cell death. Inhibition of apoptosis did not block XanX-induced autophagy in A549RT-eto cells. Furthermore, suppression of autophagy by beclin-1 small interfering RNAs (siRNAs) did not interrupt XanX-induced apoptosis, indicating that XanX can separately induce apoptosis and autophagy. Of interest, XanX treatment reduced levels of histone deacetylase 4 (HDAC4) protein overexpressed in A549RT-etocells. The co-treatment with XanX and HDAC4 siRNA accelerated both autophagy and apoptosis more than that by XanX treatment alone, suggesting survival of HDAC4 in A549RT-eto cells. XanX reverses etoposide resistance in A549RT-eto cells by induction of both autophagy and apoptosis, and confers cytotoxicity through down-regulation of HDAC4.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells
Kaewpiboon, C.,Surapinit, S.,Malilas, W.,Moon, J.,Phuwapraisirisan, P.,Tip-Pyang, S.,Johnston, R.N.,Koh, S.S.,Assavalapsakul, W.,Chung, Y.-H. Spandidos Publications 2014 International journal of oncology Vol.44 No.4
KAEWPIBOON, CHUTIMA,SRISUTTEE, RATAKORN,MALILAS, WARAPORN,MOON, JEONG,OH, SANGTAEK,JEONG, HYE GWANG,JOHNSTON, RANDAL N.,ASSAVALAPSAKUL, WANCHAI,CHUNG, YOUNG-HWA SPANDIDOS PUBLICATIONS 2015 MOLECULAR MEDICINE REPORTS Vol.11 No.3
<P>Despite efforts to develop efficient chemotherapeutic drug strategies to treat cancer, acquired drug resistance is a commonly encountered problem. In the present study, to investigate this phenomenon, human A549 lung cancer cells resistant to the topoisomerase inhibitor etoposide (A549RT???eto) were used and compared with A549 parental cells. A549RT???eto cells demonstrated increased resistance to etoposide???induced apoptosis when compared with A549 parental cells. Notably, A549RT???eto cells were observed to exhibit greater levels of histone deacetylase 4 (HDAC4), phospho???Stat1 and P???glycoprotein [P???gp; encoded by the multidrug resistance 1 (MDR1) gene], compared with A549 cells. To address whether HDAC4 protein is involved in etoposide resistance in A549 cells, A549RT???eto cells were treated with trichostatin A (TSA; an HDAC inhibitor) during etoposide treatment. The combined treatment was demonstrated to enhance etoposide???induced apoptosis and reduce expression levels of HDAC4, P???gp and phospho???Stat1. In addition, the suppression of Stat1 with siRNA enhanced etoposide???induced apoptosis and reduced the expression levels of HDAC4 and P???gp, suggesting that Stat1 is essential in the regulation of resistance to etoposide, and in the upregulation of P???gp. Notably, TSA treatment reduced P???gp transcript levels but Stat1 siRNA treatment did not, suggesting that P???gp is regulated by HDAC at the transcriptional level and by Stat1 at the post???transcriptional level. These results suggest that the upregulation of Stat1 and HDAC4 determines etoposide resistance through P???gp expression in human A549 lung cancer cells.</P>
Kaowinn, Sirichat,Kaewpiboon, Chutima,Kim, Ji Eun,Lee, Mi Rim,Hwang, Dae Youn,Choi, Young Whan,Kim, Hong Won,Park, Jin Kyoon,Song, Kyung-Mo,Lee, Nam Hyouck,Maeng, Jin-Soo,Chung, Young-Hwa Elsevier 2018 european journal of pharmacology Vol.841 No.-
<P><B>Abstract</B></P> <P>Dietary garlic has been suggested to possess anticancer properties, and several attempts have been made to isolate the anticancer compounds. In this study, we efficiently synthesized <I>N</I>-benzyl-<I>N</I>-methyl-dodecan-1-amine (BMDA) by the reductive amination method. We evaluated the potential anticancer activities of BMDA against A549 lung cancer cells with cancer stem cell-like phenotypes due to the overexpression of cancer upregulated gene (CUG)2. <I>N</I>-Benzyl-<I>N</I>-methyl-dodecan-1-amine treatment sensitized A549 cells overexpressing CUG2 (A549-CUG2) to apoptosis and autophagy compared with those of the control cells. The treatment with BMDA also reduced tumor development in xenografted nude mice. Furthermore, BMDA inhibited cell migration, invasion, and sphere formation in A549-CUG2 cells, in which TGF-β signaling is involved. Further analysis showed that BMDA hindered TGF-β promoter activity, protein synthesis, and phosphorylation of Smad2, thus decreasing the expression of TGF-β-targeted proteins, including Snail and Twist. <I>N</I>-Benzyl-<I>N</I>-methyl-dodecan-1-amine also decreased Twist expression <I>in vivo</I>. In addition, BMDA inhibited Akt-ERK activities, β-catenin expression, and its transcriptional activity. These results suggest that BMDA can be a promising anticancer agent against cancer cells overexpressing CUG2.</P>
Kaowinn, Sirichat,Kaewpiboon, Chutima,Koh, Sang Seok,Krä,mer, Oliver H.,Chung, Young-Hwa D.A. Spandidos 2018 ONCOLOGY REPORTS Vol.40 No.5
<P>Our previous studies have shown that the novel oncogene, cancer upregulated gene 2 (CUG2), activates STAT1, which is linked to anticancer drug resistance, induces epithelial-mesenchymal transition (EMT) and cancer stem cell-like phenotypes as determined by MTT, migration and sphere formation assays. We thus aimed to ascertain whether the activation of STAT1 by CUG2 is involved in these malignant phenotypes besides drug resistance. Here, we showed that STAT1 suppression decreased the expression of N-cadherin and vimentin, biomarkers of EMT, which led to inhibition of the migration and invasion of human lung A549 cancer cells stably expressing CUG2, but did not recover E-cadherin expression. STAT1 siRNA also diminished CUG2-induced TGF-β signaling, which is critical in EMT, and TGF-β transcriptional activity. Conversely, inhibition of TGF-β signaling reduced phosphorylation of STAT1, indicating a crosstalk between STAT1 and TGF-β signaling. Furthermore, STAT1 silencing diminished sphere formation, which was supported by downregulation of stemness-related factors such as Sox2, Oct4, and Nanog. Constitutive suppression of STAT1 also inhibited cell migration, invasion and sphere formation. As STAT1 acetylation counteracts STAT1 phosphorylation, acetylation of STAT1 by treatment with trichostatin A, an inhibitor of histone deacetylases (HDACs), reduced cell migration, invasion, and sphere formation. As HDAC4 is known to target STAT1, its role was investigated under CUG2 overexpression. HDAC4 suppression resulted in inhibition of cell migration, invasion, and sphere formation as HDAC4 silencing hindered TGF-β signaling and decreased expression of Sox2 and Nanog. Taken together, we suggest that STAT1-HDAC4 signaling induces malignant tumor features such as EMT and sphere formation in CUG2-overexpressing cancer cells.</P>
Moon, J.,Koh, S.S.,Malilas, W.,Cho, I.R.,Kaewpiboon, C.,Kaowinn, S.,Lee, K.,Jhun, B.H.,Choi, Y.W.,Chung, Y.H. North-Holland ; Elsevier Science Ltd 2014 european journal of pharmacology Vol.735 No.-
Since it has been known that shikonin derived from a medicinal plant possesses anti-cancer activity, we wonder whether acetylshikonin (ASK), a derivate of shikonin, can be used to treat hepatocellular carcinoma cells expressing hepatitis B virus X protein (HBX), an oncoprotein from hepatitis B virus. When ASK was added to Hep3B cells stably expressing HBX, it induced apoptosis in a dose-dependent manner. ASK induced upregulation and export of Nur77 to the cytoplasm and activation of JNK. Likewise, suppression of Nur77 and JNK inactivation protected the cells from ASK-induced apoptosis, indicating that Nur77 upregulation and JNK activation were required for ASK-mediated apoptosis. Furthermore, ASK increased the expression of Bip and ubiquitination levels of cellular proteins, features of endoplasmic reticulum (ER) stress, via the production of reactive oxygen species in a dose-dependent manner. Suppression of reactive oxygen species with N-acetylcysteine reduced levels of Bip protein and ubiquitination levels of cellular proteins during ASK treatment, leading to protection of cells from apoptosis. Cycloheximide treatment reduced ASK-induced ER stress, suggesting that protein synthesis is involved in ASK-induced ER stress. Moreover, we showed using salubrinal, an ER stress inhibitor that reactive oxygen species production, JNK activation, and Nur77 upregulation and its translocation to cytoplasm are necessary for ER-induced stress. Interestingly, we found that JNK inactivation suppresses ASK-induced ER stress, whereas Nur77 siRNA treatment does not, indicating that JNK is required for ASK-induced ER stress. Accordingly, we report that ASK induces ER stress, which is prerequisite for apoptosis of HBX-expressing hepatocellular carcinoma cells.
Moon, J.,Kaowinn, S.,Cho, I.R.,Min, D.S.,Myung, H.,Oh, S.,Kaewpiboon, C.,Kraemer, O.H.,Chung, Y.H. Academic Press 2016 Biochemical and biophysical research communication Vol.474 No.3
Since hepatitis C virus (HCV) core protein is known to possess potential oncogenic activity, we explored whether oncolytic vesicular stomatitis virus (VSV) could efficiently induce cytolysis in hepatocellular carcinoma cells stably expressing HCV core protein (Hep3B-Core). We found that Hep3B-Core cells were more susceptible to VSV as compared to control (Hep3B-Vec) cells owing to core-mediated inactivation of STAT1 and STAT2 proteins. Core expression induced lower phosphorylation levels of type I IFN signaling proteins such as Tyk2 and Jak1, and a reduced response to exogenous IFN-α, which resulted in susceptibility to VSV. Furthermore, as STAT1 acetylation by switching phosphorylation regulated its activity, the role of STAT1 acetylation in susceptibility of Hep3B-Core cells to VSV was investigated. Treatment with trichostatin A, an inhibitor of histone deacetylase (HDAC), increased STAT1 acetylation but blocked IFN-α-induced phosphorylation of STAT1, leading to increase of susceptibility to VSV. Interestingly, the core protein decreased HDCA4 transcript levels, leading to down-regulation of HDAC4 protein. However, ectopic expression of HDAC4 conversely enforced phosphorylation of STAT1 and hindered VSV replication, indicating that core-mediated reduction of HDAC4 provides a suitable intracellular circumstance for VSV replication. Collectively, we suggest that VSV treatment will be a useful therapeutic strategy for HCV-infected hepatocellular carcinoma cells because HCV core protein suppresses the anti-viral threshold by down-regulation of the STAT1-HDAC4 signaling axis.