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Sin-Aye Park 대한의생명과학회 2018 Biomedical Science Letters Vol.24 No.4
Gremlin-1 (GREM1) has been defined as an antagonist of bone morphogenetic proteins (BMPs), particularly during embryonic development and tissue differentiation. However, recent studies have shown that GREM1 has BMPs-dependent or -independent functions in diverse human diseases. GREM1 plays a key role in the process of organ fibrosis, including lungs, kidneys, and so on. The GREM1-induced fibrosis typically promotes the development of other diseases, such as pulmonary hypertension, renal inflammation, and diabetic nephropathy. More recently, considerable evidence has been reported showing that GREM1 is involved in the promotion and/or progression of tumors in vitro and in vivo. It also performs an oncogenic role in the maintenance of cancer stem cells. Although GREM1 is known to function in a variety of diseases, here we focus on the role of GREM1 in cancer, and suggest GREM1 as a potential therapeutic target in certain types of cancer.
Catechol Estrogen 4-Hydroxyestradiol is an Ultimate Carcinogen in Breast Cancer
Sin-Aye Park 대한의생명과학회 2018 Biomedical Science Letters Vol.24 No.3
Excessive exposure to estrogens is the most important risk factor for the development of hormone-sensitive cancers, especially breast cancer. Estrogen stimulates the expression of genes and proteins involved in cell proliferation by binding to estrogen receptor (ER). Another possible mechanism of ER-independent carcinogenicity of estrogens is based on the hydroxylation of estradiol resulting in the formation of catechol estrogens. Catechol estrogen 4-hydroxyestradiol (4-OHE₂) is further oxidized to catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. Evidence increasingly supports the critical role of 4-OHE₂ in hormonal carcinogenesis via DNA adduct formation or production of reactive oxygen species, which finally contribute to the transformation of normal mammary epithelial cells and the enhanced growth of breast cancer cells. It is also reported that the level of 4-OHE₂ or its quinones is highly up-regulated in urine or tissues of breast cancer patients. Thus, we highlight the oncogenic roles of 4-OHE₂ in catechol estrogen-induced breast carcinogenesis.
Park, Sin-Aye,Na, Hye-Kyung,Surh, Young-Joon Informa Healthcare 2012 Free radical research Vol.46 No.8
<P>Excess estrogen stimulates the proliferation of mammary epithelial cells and hence represents a major risk factor for breast cancer. Estrogen is subjected to cytochrome P450-catalysed oxidative metabolism to produce an oncogenic catechol estrogen, 4-hydroxyestradiol (4-OHE<SUB>2</SUB>). 4-OHE<SUB>2</SUB> undergoes redox cycling during which reactive oxygen species (ROS) as well as the chemically reactive estrogen semiquinone and quinone intermediates are produced, thereby contributing to hormonal carcinogenesis. Resveratrol (3,4′,5-trihydroxy stilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the inhibitory effects of resveratrol on 4-OHE<SUB>2</SUB>-induced transformation of human breast epithelial MCF-10A cells. Resveratrol inhibited migration and anchorage-independent growth of MCF-10A cells treated with 4-OHE<SUB>2</SUB>. Resveratrol treatment suppressed the 4-OHE<SUB>2</SUB>-induced activation of IκB kinaseβ (IKKβ) and phosphorylation of IκBα, and consequently NF-κB DNA binding activity and cyclooxygenase-2 (COX-2) expression. Resveratrol suppressed ROS production and phosphorylation of Akt and ERK induced by 4-OHE<SUB>2</SUB> treatment. In conclusion, resveratrol blocks activation of IKKβ-NF-κB signalling and induction of COX-2 expression in 4-OHE<SUB>2</SUB>-treated MCF-10A cells, thereby suppressing migration and transformation of these cells.</P>
Almazari, Inas,Park, Jong-Min,Park, Sin-Aye,Suh, Jin-Young,Na, Hye-Kyung,Cha, Young-Nam,Surh, Young-Joon IRL Press] ; Oxford University Press 2012 Carcinogenesis Vol.33 No.2
<P>Guggulsterone (GS) [4,17(20)-pregnadiene-3,16-dione] is a phytosterol found in the gum resin of the Commiphora mukul. GS exists naturally in two stereoisomers: E-GS (cis-GS) and Z-GS (trans-GS). In this study, the effects of both isomers on expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) were evaluated in human mammary epithelial (MCF10A) cells. NF-E2-related factor 2 (Nrf2) is considered a master regulator in activating antioxidant response element (ARE)-driven expression of HO-1 and many other antioxidant/cytoprotective proteins. cis-GS upregulated the transcription and protein expression of HO-1 to a greater extent than did trans-GS. cis-GS treatment enhanced nuclear translocation and ARE-binding activity of Nrf2. MCF10A cells transfected with an ARE luciferase construct exhibited significantly elevated Nrf2 transcriptional activity upon cis-GS treatment compared with cells transfected with the control vector. In addition, silencing of the Nrf2 gene abrogated cis-GS-induced expression of HO-1. Incubation of MCF10A cells with cis-GS increased phosphorylation of Akt. The pharmacological inhibition of phosphoinositide 3-kinase (PI3K), an upstream kinase responsible for Akt phosphorylation, abrogated cis-GS-induced Nrf2 nuclear translocation. Pretreatment with the thiol-reducing agents attenuated Akt phosphorylation, Nrf2 activation and HO-1 expression, suggesting that cis-GS may cause thiol modification of an upstream signaling modulator. Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) is a negative regulator of the PI3K-Akt axis. The mutation in cysteine 124 present in the catalytic domain of PTEN abolished cis-GS-induced HO-1 expression as well as Akt phosphorylation. Whether this cysteine is a 'bona fide' target of cis-GS in its activation of Nrf2 needs additional investigation.</P>
Dehydrocostus Lactone Suppresses the Expression of iNOS Induced by TLR Agonists
Su Yeon Kim,Sunghye Heo,Seung Han Kim,Minji Kwon,Sin-Aye Park,Hyung-Sun Youn 대한의생명과학회 2019 Biomedical Science Letters Vol.25 No.3
Toll-like receptors (TLRs) are one of the families of pattern recognition receptors (PRR) to recognize pathogenassociated molecular patterns (PAMPs). PAMPs stimulate TLRs to initiate specific immunoactivity. The activation of TLRs signaling leads to the expression of pro-inflammatory gene products such as cytokines and inducible nitric oxide synthase (iNOS). To evaluate the therapeutic potential of dehydrocostus lactone (DHL), which is a natural sesquiterpene lactone derived from various medicinal plants, iNOS expression induced by LPS (TLR4 agonist), MALP-2 (TLR2 and TLR6 agonist), or Poly[I:C] (TLR3 agonist) were examined. DHL suppressed the iNOS expression induced by LPS, MALP-2, or Poly[I:C]. DHL also inhibited nitrite production induced by LPS, MALP-2, or Poly[I:C]. These results suggest that DHL can modulate TLRs signaling pathways resulting in anti-inflammatory effect.
Suh, Jinyoung,Kim, Do-Hee,Kim, Eun-Hee,Park, Sin-Aye,Park, Jong-Min,Jang, Jeong-Hoon,Kim, Su-Jung,Na, Hye-Kyung,Kim, Nam-Doo,Kim, Nam-Jung,Suh, Young Ger,Surh, Young-Joon Elsevier 2018 Cancer letters Vol.424 No.-
<P><B>Abstract</B></P> <P>15-Deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> (15d-PGJ<SUB>2</SUB>), one of the terminal products of cyclooxygenase-2-catalized arachidonic acid metabolism, has been shown to stimulate breast cancer cell proliferation and migration through Akt activation, but the underlying mechanisms remain poorly understood. In the present study, we investigated the effects of 15d-PGJ<SUB>2</SUB> on the activity of PTEN, the inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt axis, in human breast cancer (MCF-7) cells. Since the α,β-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ<SUB>2</SUB> is electrophilic, we hypothesized that 15d-PGJ<SUB>2</SUB>-induced Akt phosphorylation might result from the covalent modification and subsequent inactivation of PTEN that has several critical cysteine residues. When treated to MCF-7 cells, 15d-PGJ<SUB>2</SUB> bound to PTEN, and this was abolished in the presence of the thiol-reducing agent dithiothreitol. A mass spectrometric analysis by using recombinant and endogenous PTEN protein revealed that the cysteine 136 residue (Cys<SUP>136</SUP>) of PTEN is covalently modified upon treatment with 15d-PGJ<SUB>2</SUB>. Notably, the ability of 15d-PGJ<SUB>2</SUB> to covalently bind to PTEN as well as to induce Akt phosphorylation was abolished in the cells expressing a mutant form of PTEN in which Cys<SUP>136</SUP> was replaced by serine (C136S-PTEN). The present study demonstrates for the first time that electrophilic 15d-PGJ<SUB>2</SUB> directly binds to cysteine 136 of PTEN and provides new insight into PTEN loss in cancer progression associated with chronic inflammation. These observations suggest that 15d-PGJ<SUB>2</SUB> can undergo nucleophilic addition to PTEN, presumably at Cys<SUP>136</SUP>, thereby inactivating this tumor suppressor protein with concomitant Akt activation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> PTEN is inactivated through covalent modification by 15-deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> in breast cancer MCF-7 cells. </LI> <LI> 15-Deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> directly binds to the cysteine 136 residue of the recombinant PTEN. </LI> <LI> PTEN interaction with 15-deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> stimulates Akt phosphorylation. </LI> <LI> 15-Deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> stimulates growth of MDA-MB-231 cells when inoculated to the athymic nude mice. </LI> </UL> </P>