15-Deoxy-Δ^12,14-prostaglandin J₂ stabilizes, but functionally inactivates p53 by binding to the cysteine 277 residue

Kim, D-H,Kim, E-H,Na, H-K,Sun, Y,Surh, Y-J Macmillan Publishers Limited 2010 Oncogene Vol.29 No.17

15-Deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> (15d-PGJ<SUB>2</SUB>), a representative cyclopentenone prostaglandin, has many interesting biological effects. In this study, treatment of human breast cancer cells (MCF-7) with 15d-PGJ<SUB>2</SUB> led to accumulation of p53 protein. However, the p53 DNA binding and its transcriptional activity were significantly reduced. 15d-PGJ<SUB>2</SUB> directly modified p53 as verified by reacting recombinant p53 with biotinylated 15d-PGJ<SUB>2</SUB>. 9,10-Dihydro-15-deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> lacking the electrophilic α,β-unsaturated functionality failed to inhibit p53 DNA binding as well as to modify p53. Moreover, by conducting an in vitro [<SUP>35</SUP>S]-labeled p53 translation assay, we identified cysteine 277 as a putative site of p53 modification by 15d-PGJ<SUB>2</SUB>. The DNA-binding ability of a mutant p53 in which cysteine 277 was substituted by alanine was virtually unaffected by 15d-PGJ<SUB>2</SUB>. Likewise, p53 binding activity of biotinylated 15d-PGJ<SUB>2</SUB> was abolished in mutant cells. In addition, cells expressing wild-type p53 exhibited p53 protein stability to a greater extent than mutant C277A cells. In conclusion, 15d-PGJ<SUB>2</SUB> can undergo nucleophilic addition to p53, presumably at the cysteine 277 residue, rendering this tumor suppressor less susceptible to proteasomal degradation.

15-Deoxy-Δ^12,14-prostaglandin J₂ induces expression of 15-hydroxyprostaglandin dehydrogenase through Elk-1 activation in human breast cancer MDA-MB-231 cells

Kim, H.R.,Lee, H.N.,Lim, K.,Surh, Y.J.,Na, H.K. Elsevier Science Publishers 2014 Mutation Research Vol.768 No.-

Overproduction of prostaglandin E<SUB>2</SUB> (PGE<SUB>2</SUB>) has been reported to be implicated in carcinogenesis. The intracellular level of PGE<SUB>2</SUB> is maintained not only by its biosynthesis, but also by inactivation/degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of oncogenic PGE<SUB>2</SUB> to a biologically inactive keto metabolite. In the present study, we demonstrate that 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, updregulates the expression and the activity of 15-PGDH in human breast cancer MDA-MB-231 cells. By using deletion constructs of the 15-PGDH promoter, we have found that E-twenty six (Ets) is the most essential determinant for 15-PGDH induction. 15d-PGJ<SUB>2</SUB> induced phosphorylation of Elk-1, one of Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15d-PGJ<SUB>2</SUB> to upregulate 15-PGDH expression. Furthermore, 15d-PGJ<SUB>2</SUB>-mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) ½. Treatment of U0126, a pharmacological inhibitor of MEK½-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15d-PGJ<SUB>2</SUB>-treated MDA-MB-231 cells. Moreover, 15d-PGJ<SUB>2</SUB> generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK½ and Elk-1. 15d-PGJ<SUB>2</SUB> inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with 15-PGDH siRNA. Taken together, these findings suggest that 15d-PGJ<SUB>2</SUB> induces the expression of 15-PGDH through ROS-mediated activation of ERK½ and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin.

15-Deoxy-Δ^12,14-prostaglandin J₂ induces p53 expression through Nrf2-mediated upregulation of heme oxygenase-1 in human breast cancer cells

Kim, D. H.,Song, N. Y.,Kim, E. H.,Na, H. K.,Joe, Y.,Chung, H. T.,Surh, Y. J. Informa Healthcare 2014 Free radical research Vol.48 No.9

<P>Heme oxygenase-1 (HO-1) is a stress-responsive enzyme that has antioxidant and cytoprotective functions. However, HO-1 has oncogenic functions in cancerous or transformed cells. In the present work, we investigated the effects of HO-1 on the expression of p53 induced by 15-deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> (15d-PGJ<SUB>2</SUB>) in human breast cancer (MCF-7) cells. Treatment of MCF-7 cells with 15d-PGJ<SUB>2</SUB> led to time-dependent increases in the expression of p53 as well as HO-1. Upregulation of p53 expression by 15d-PGJ<SUB>2</SUB> was abrogated by si-RNA knock-down of HO-1. In MCF-7 cells transfected with HO-1 si-RNA, 15d-PGJ<SUB>2</SUB> failed to induce expression of p53 as well as HO-1. In addition, HO-1 inducers enhanced the p53 expression. We speculated that iron, a by-product of HO-1-catalyzed reactions, could mediate 15d-PGJ<SUB>2</SUB>-induced p53 expression. Upregulation of p53 expression by 15d-PGJ<SUB>2</SUB> was abrogated by the iron chelator desferrioxamine in MCF-7 cells. Iron released from heme by HO-1 activity is mostly in the Fe<SUP>2+</SUP> form. When MCF-7 cells were treated with the Fe<SUP>2+</SUP>-specific chelator phenanthroline, 15d-PGJ<SUB>2</SUB>-induced p53 expression was attenuated. In addition, levels of the Fe-sequestering protein H-ferritin were elevated in 15d-PGJ<SUB>2</SUB>-treated MCF-7 cells. In conclusion, upregulation of p53 and p21 via HO-1 induction and subsequent release of iron with accumulation of H-ferritin may confer resistance to oxidative damage in cancer cells frequently challenged by redox-cycling anticancer drugs.</P>

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

Lee, K-S,Lee, Y-S,Lee, J-M,Ito, K,Cinghu, S,Kim, J-H,Jang, J-W,Li, Y-H,Goh, Y-M,Chi, X-Z,Wee, H,Lee, H-W,Hosoya, A,Chung, J-H,Jang, J-J,Kundu, J K,Surh, Y-J,Kim, W-J,Ito, Y,Jung, H-S,Bae, S-C Macmillan Publishers Limited 2010 Oncogene Vol.29 No.23

Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3−/− mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3−/− bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3−/− epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3+/− mice (∼18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3+/− mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.

Redox-Sensitive Transcription Factors as Prime Targets for Chemoprevention with Anti-Inflammatory and Antioxidative Phytochemicals

Surh, Y.-J.,Kundu, J. K.,Na, H.-K.,Lee, J.-S. AMERICAN INSTITUTE OF NUTRITION 2005 The Journal of nutrition Vol.135 No.12

New J and COD estimates for thin-walled pipes with axial through-wall cracks and high strain hardening exponents

Surh, H.B.,Jang, Y.Y.,Kim, S.C.,Shim, D.J.,Huh, N.S. Elsevier Science Publishers B.V. (North-Holland) 2017 Theoretical and applied fracture mechanics Vol.90 No.-

<P>In this study, the approximate estimates of elastic-plastic J and COD for thin-walled pipes with axial through-wall cracks (TWCs) and high strain hardening exponents under internal pressure are developed based on the GE/EPRI and enhanced reference stress (ERS) methods. For the estimations based on the GE/EPRI method, the proposed tabulated plastic influence functions for fully plastic J and COD are derived from three-dimensional finite element(FE) analyses. On the basis of these plastic influence functions, an optimized reference load (which plays an important role in the ERS method) is newly suggested. Finally, the present elastic-plastic J and COD estimations are verified by comparing the predicted results with the FE results using actual tensile behavior of SA312 type 304 SAW stainless steel. The estimations based on both GE/EPRI and ERS methods provide better approximations for thin-walled pipes with axial TWC and high strain hardening exponent, than do the existing estimations. The importance of the elastic plastic fracture mechanics assessment, using the present solutions for thin-walled pipe with axial TWC and high strain hardening exponent, are also discussed. (C) 2017 Elsevier Ltd. All rights reserved.</P>

A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders

Kim, J.,Cha, Y.N.,Surh, Y.J. Elsevier Science Publishers 2010 Mutation research Vol.690 No.1

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor that plays a central role in cellular defense against oxidative and electrophilic insults by timely induction of antioxidative and phase-2 detoxifying enzymes and related stress-response proteins. The 5'-flanking regions of genes encoding these cytoprotective proteins contain a specific consensus sequence termed antioxidant response element (ARE) to which Nrf2 binds. Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries. During the early-phase of inflammation-mediated tissue damage, activation of Nrf2-ARE might inhibit the production or expression of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide synthase. It is likely that the cytoprotective function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the induction of pro-inflammatory genes. This review highlights the protective role of Nrf2 in inflammation-mediated disorders with special focus on the inflammatory signaling modulated by this redox-regulated transcription factor.

Poster Presentation Abstracts ; CAPSAICIN INDUCES APOPTOSIS IN RAS - TRANSFORMED HUMAN BREAST EPITHELIAL CELLS VIA ACTIVATION OF C - JUN N - TERMINAL PROTEIN KINASE

(H . J . Jang),(Y . Soh),(M . S . Kim),(Y . J . Surh),(H . R . Choi Kim),(A . Moon) 한국응용약물학회 1999 학술대회 Vol.1999 No.2

Multidirectional tumor-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis

Choi, J. W.,Um, J. Y.,Kundu, J. K.,Surh, Y.-J.,Kim, S. Oxford University Press 2009 Carcinogenesis Vol.30 No.9

<P>Aminoacyl-transfer ribonucleic acid (tRNA) synthetases-interacting multifunctional protein (AIMP) 2 is a factor associated with the macromolecular protein synthesis machinery consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. However, it was shown to work as a multifaceted regulator through the versatile interactions with diverse signal mediators. For instance, it can mediate pro-apoptotic response to DNA damage and tumor necrosis factor-alpha (TNF-alpha) stimulus and growth-arresting signal by transforming growth factor (TGF)-beta. Considering that these pathways are critically implicated in the control of tumorigenesis, AIMP2 is expected to work as a potent tumor suppressor with broad coverage against different cancer types. Here we investigated whether AIMP2 would give gene dosage effect on its pro-apoptotic and anti-proliferative activities using the wild-type, hetero- and homozygous AIMP2 cells and whether AIMP2 would be critical in preventing tumorigenesis using different in vivo tumor models. Both the apoptotic responses to DNA damage and TNF-alpha and sensitivity to growth arresting TGF-beta signal were reduced in AIMP2 hetero- and homozygous cells compared with the wild-type cells in dose-dependent manner. In all the in vivo carcinogenesis experiments, reduction of AIMP2 level in heterozygous AIMP2 mice provided higher susceptibility to tumor formation. Thus, this work proves the functional significance of AIMP2 in determination of cell proliferation and death, and as a haploinsufficient tumor suppressor.</P>

Suppression of mTOR via Akt-dependent and -independent mechanisms in selenium-treated colon cancer cells: involvement of AMPKa1

Lee, Y. K.,Park, S. Y.,Kim, Y. M.,Kim, D. C.,Lee, W. S.,Surh, Y. J.,Park, O. J. Oxford University Press 2010 Carcinogenesis Vol.31 No.6