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Liu, Haidan,Hwang, Joonsung,Li, Wei,Choi, Tae Woong,Liu, Kangdong,Huang, Zunnan,Jang, Jae-Hyuk,Thimmegowda, N.R.,Lee, Ki Won,Ryoo, In-Ja,Ahn, Jong-Seog,Bode, Ann M.,Zhou, Xinmin,Yang, Yifeng,Erikson, American Association for Cancer Research 2014 CANCER PREVENTION RESEARCH Vol.7 No.1
<P>Mitogen- and stress-activated kinase 1 (MSK1) is a nuclear serine/threonine protein kinase that acts downstream of both extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in response to stress or mitogenic extracellular stimuli. Increasing evidence has shown that MSK1 is closely associated with malignant transformation and cancer development. MSK1 should be an effective target for cancer chemoprevention and chemotherapy. However, very few MSK1 inhibitors, especially natural compounds, have been reported. We used virtual screening of a natural products database and the active conformation of the C-terminal kinase domain of MSK1 (PDB id 3KN) as the receptor structure to identify chrysin and its derivative, compound 69407, as inhibitors of MSK1. Compared with chrysin, compound 69407 more strongly inhibited proliferation and 12-<I>O</I>-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells with lower cytotoxicity. Western blot data demonstrated that compound 69407 suppressed phosphorylation of the MSK1 downstream effector histone H3 in intact cells. Knocking down the expression of MSK1 effectively reduced the sensitivity of JB6 P+ cells to compound 69407. Moreover, topical treatment with compound 69407 before TPA application significantly reduced papilloma development in terms of number and size in a two-stage mouse skin carcinogenesis model. The reduction in papilloma development was accompanied by the inhibition of histone H3 phosphorylation at Ser10 in tumors extracted from mouse skin. The results indicated that compound 69407 exerts inhibitory effects on skin tumorigenesis by directly binding with MSK1 and attenuates the MSK1/histone H3 signaling pathway, which makes it an ideal chemopreventive agent against skin cancer. <I>Cancer Prev Res; 7(1); 74–85. ©2013 AACR</I>.</P>
Aloe-emodin suppresses prostate cancer by targeting the mTOR complex 2.
Liu, Kangdong,Park, Chanmi,Li, Shengqing,Lee, Ki Won,Liu, Haidan,He, Long,Soung, Nak Kyun,Ahn, Jong Seog,Bode, Ann M,Dong, Ziming,Kim, Bo Yeon,Dong, Zigang IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.7
<P>Phosphatidylinositol 3-kinase (PI3-K) amplification and phosphatase and tensin homolog (PTEN) deletion-caused Akt activation contribute to the development of prostate cancer. Mammalian target of rapamycin complex 2 (mTORC2) is a kinase complex comprised of mTOR, Rictor, mSin1, mLST8/G관L and PRR5 and functions in the phosphorylation of Akt at Ser473. Herein, we report that mTORC2 plays an important role in PC3 androgen refractory prostate cell proliferation and anchorage-independent growth. Aloe-emodin, a natural compound found in aloe, inhibited both proliferation and anchorage-independent growth of PC3 cells. Protein content analysis suggested that activation of the downstream substrates of mTORC2, Akt and PKC관, was inhibited by aloe-emodin treatment. Pull-down assay and in vitro kinase assay results indicated that aloe-emodin could bind with mTORC2 in cells and inhibit its kinase activity. Aloe-emodin also exhibited tumor suppression effects in vivo in an athymic nude mouse model. Collectively, our data suggest that mTORC2 plays an important role in prostate cancer development and aloe-emodin suppresses prostate cancer progression by targeting mTORC2.</P>
Ma, Chaobing,Zu, Xueyin,Liu, Kangdong,Bode, Ann M.,Dong, Zigang,Liu, Zhenzhen,Kim, Dong Joon Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.9
Altered genetic features in cancer cells lead to a high rate of aerobic glycolysis and metabolic reprogramming that is essential for increased cancer cell viability and rapid proliferation. Pyruvate kinase muscle (PKM) is a rate-limiting enzyme in the final step of glycolysis. Herein, we report that PKM is a potential therapeutic target in triple-negative breast cancer (TNBC) cells. We found that PKM1 or PKM2 is highly expressed in TNBC tissues or cells. Knockdown of PKM significantly suppressed cell proliferation and migration, and strongly reduced S phase and induced G2 phase cell cycle arrest by reducing phosphorylation of the CDC2 protein in TNBC cells. Additionally, knockdown of PKM significantly suppressed $NF-{\kappa}B$ (nuclear factor kappa-light-chain-enhancer of activated B cells) activity by reducing the phosphorylation of p65 at serine 536, and also decreased the expression of $NF-{\kappa}B$ target genes. Taken together, PKM is a potential target that may have therapeutic implications for TNBC cells.
Chaobing Ma,Xueyin Zu,Kangdong Liu,Ann M. Bode,지강동,Zhenzhen Liu,김동준 한국분자세포생물학회 2019 Molecules and cells Vol.42 No.9
Altered genetic features in cancer cells lead to a high rate of aerobic glycolysis and metabolic reprogramming that is essential for increased cancer cell viability and rapid proliferation. Pyruvate kinase muscle (PKM) is a rate-limiting enzyme in the final step of glycolysis. Herein, we report that PKM is a potential therapeutic target in triple-negative breast cancer (TNBC) cells. We found that PKM1 or PKM2 is highly expressed in TNBC tissues or cells. Knockdown of PKM significantly suppressed cell proliferation and migration, and strongly reduced S phase and induced G2 phase cell cycle arrest by reducing phosphorylation of the CDC2 protein in TNBC cells. Additionally, knockdown of PKM significantly suppressed NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity by reducing the phosphorylation of p65 at serine 536, and also decreased the expression of NF-kB target genes. Taken together, PKM is a potential target that may have therapeutic implications for TNBC cells.
Lim, Tae-Gyu,Lee, Sung-Young,Duan, Zhaoheng,Lee, Mee-Hyun,Chen, Hanyong,Liu, Fangfang,Liu, Kangdong,Jung, Sung Keun,Kim, Dong Joon,Bode, Ann M.,Lee, Ki Won,Dong, Zigang AMERICAN ASSOCIATION FOR CANCER RESEARCH INC 2017 CANCER PREVENTION RESEARCH Vol.10 No.5
<P>Intake of soy isoflavones is inversely associated with the risk of esophageal cancer. Numerous experimental results have supported the anticancer activity of soy isoflavones. This study aimed to determine the anti-esophageal cancer activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), a major metabolite of daidzein, which is readily metabolized in the human body. Notably, 6,7,4'-THIF inhibited proliferation and increased apoptosis of esophageal cancer cells. On the basis of a virtual screening analysis, Pin1 was identified as a target protein of 6,7,4'-THIF. Pull-down assay results using 6,7,4'-THIF Sepharose 4B beads showed a direct interaction between 6,7,4'-THIF and the Pin1 protein. Pin1 is a critical therapeutic and preventive target in esophageal cancer because of its positive regulation of beta-catenin and cyclin D1. The 6,7,4'-THIF compound simultaneously reduced Pin1 isomerase activity and the downstream activation targets of Pin1. The specific inhibitory activity of 6,7,4'-THIF was analyzed using Neu/Pin1 wild-type (WT) and Neu/Pin1 knockout (KO) MEFs. 6,7,4'-THIF effected Neu/Pin1 WT MEFs, but not Neu/Pin1 KO MEFs. Furthermore, the results of a xenograft assay using Neu/Pin1 WT and KO MEFs were similar to those obtained from the in vitro assay. Overall, we found that 6,7,4'-THIF specifically reduced Pin1 activity in esophageal cancer models. Importantly, 6,7,4'-THIF directly bound to Pin1 but not FKBP or cyclophilin A, the same family of proteins. Because Pin1 acts like an oncogene by modulating various carcinogenesis-related proteins, this study might at least partially explain the underlying mechanism(s) of the anti-esophageal cancer effects of soy isoflavones. (C) 2017 AACR.</P>
Haibo Zhang,Junkoo Yi,휘앙하이,Si Jun Park,권욱봉,김은경,So-Young Jang,Si-Yong Kim,최성균,Du-Hak Yoon,Sung-Hyun Kim,Kangdong Liu,Zigang Dong,Zae Young Ryoo,Myoung Ok Kim 고려인삼학회 2022 Journal of Ginseng Research Vol.46 No.3
Colorectal cancer (CRC) has a high morbidity and mortality worldwide. 20 (S)-ginsenosideRh2 (G-Rh2) is a natural compound extracted from ginseng, which exhibits anticancer effects in manycancer types. In this study, we demonstrated the effect and underlying molecular mechanism of G-Rh2 inCRC cells in vitro and in vivo. Methods: Cell proliferation, migration, invasion, apoptosis, cell cycle, and western blot assays wereperformed to evaluate the effect of G-Rh2 on CRC cells. In vitro pull-down assay was used to verify theinteraction between G-Rh2 and Axl. Transfection and infection experiments were used to explore thefunction of Axl in CRC cells. CRC xenograft models were used to further investigate the effect of Axlknockdown and G-Rh2 on tumor growth in vivo. Results: G-Rh2 significantly inhibited proliferation, migration, and invasion, and induced apoptosis andG0/G1 phase cell cycle arrest in CRC cell lines. G-Rh2 directly binds to Axl and inhibits the Axl signalingpathway in CRC cells. Knockdown of Axl suppressed the growth, migration and invasion ability of CRCcells in vitro and xenograft tumor growth in vivo, whereas overexpression of Axl promoted the growth,migration, and invasion ability of CRC cells. Moreover, G-Rh2 significantly suppressed CRC xenografttumor growth by inhibiting Axl signaling with no obvious toxicity to nude mice. Conclusion: Our results indicate that G-Rh2 exerts anticancer activity in vitro and in vivo by suppressingthe Axl signaling pathway. G-Rh2 is a promising candidate for CRC prevention and treatment.
Park, Chan-Mi,Kim, Hye-Min,Kim, Dong Hyun,Han, Ho-Jin,Noh, Haneul,Jang, Jae-Hyuk,Park, Soo-Hyun,Chae, Han-Jung,Chae, Soo-Wan,Ryu, Eun Kyoung,Lee, Sangku,Liu, Kangdong,Liu, Haidan,Ahn, Jong-Seog,Kim, Y Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.12
Ginsenosides, which are the active materials of ginseng, have biological functions that include anti-osteoporotic effects. Aqueous ginseng extract inhibits osteoclast differentiation induced by receptor activator of NF-${\kappa}B$ ligand (RANKL). Aqueous ginseng extract produces chromatography peaks characteristic of ginsenosides. Among these peaks, ginsenoside Re is a major component. However, the preventive effects of ginsenoside Re against osteoclast differentiation are not known. We studied the effect of ginsenoside Re on osteoclast differentiation, RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity, and formation of multinucleated osteoclasts in vitro. Ginsenoside Re hampered osteoclast differentiation in a dose-dependent manner. In an in vivo zebrafish model, aqueous ginseng extract and ginsenoside Re had anti-osteoclastogenesis effects. These findings suggest that both aqueous ginseng extract and ginsenoside Re prevent bone resorption by inhibiting osteoclast differentiation. Ginsenoside Re could be important for promoting bone health.