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Therapeutic inhibition of SGK1 suppresses colorectal cancer.

Xuchun LIANG ; Chunling LAN ; Guanming JIAO ; Wencheng FU ; Xuesha LONG ; Yu AN ; Kejin WANG ; Jinzhe ZHOU ; Ting CHEN ; Yongqin LI ; Jiahong XU ; Qi HUANG ; Bin XU ; Junjie XIAO

Experimental & Molecular Medicine.2017;49(11):e399-. doi:10.1038/emm.2017.184

Colorectal cancer (CRC) is one of the leading causes of death worldwide. Thus, the development of new therapeutic targets for CRC treatment is urgently needed. SGK1 is involved in various cellular activities, and its dysregulation can result in multiple cancers. However, little is known about its roles and associated molecular mechanisms in CRC. In present study, we found that SGK1 was highly expressed in tumor tissues compared with peri-tumor samples from CRC patients. In vitro experiments revealed that SGK1 overexpression promoted colonic tumor cell proliferation and migration and inhibited cell apoptosis induced by 5-fluorouracil (5-FU), while SGK1 shRNA and inhibitors showed the inverse effects. Using CRC xenograft mice models, we demonstrated that knockdown or therapeutic inhibition of SGK1 repressed tumor cell proliferation and tumor growth. Moreover, SGK1 inhibitors increased p27 expression and promoted p27 nuclear accumulation in colorectal cancer cells, and p27 siRNAs could attenuate the repression of CRC cell proliferation induced by SGK1 inhibitors. Collectively, SGK1 promotes colorectal cancer development via regulation of CRC cell proliferation, migration and survival. Inhibition of SGK1 represents a novel strategy for the treatment of CRC.
Animals ; Apoptosis ; Cause of Death ; Cell Proliferation ; Colon ; Colorectal Neoplasms* ; Fluorouracil ; Heterografts ; Humans ; In Vitro Techniques ; Mice ; Repression, Psychology ; RNA, Small Interfering

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Homo-dimerization of RyR1 C-terminus via charged residues in random coils or in an alpha-helix.

Eun Hui LEE ; Paul D ALLEN

Experimental & Molecular Medicine.2007;39(5):594-602.

To investigate the mechanism by which the C-terminus (4,938-5,037) of the ryanodine receptor 1 (RyR1) homo-tetramerizes, forming a functional Ca2+ -release channel, the structural requirements for the tetramerization were studied using site-directed mutagenesis. Alanine-substitutions at five charged residues, E4976, H5003, D5026, E5033 and D5034, significantly decreased the formation of homo-dimers (reduced by > 50%). Interaction between the C-terminus and cytoplasmic loop I (4,821-4,835) required two positively charged residues, H4832 and K4835. Based on the predicted protein secondary structures, all seven charged residues are located in random coils. Paired alanine-substitutions at six negatively charged residues (E4942A/D4953A, D4945A/E4952A and E4948A/ E4955A) of the alpha-helix (4,940-4,956) in the C-terminus increased homo-dimerization. Therefore, the homo-tetramerization of RyR1 may be mediated by intra- and/or inter-monomer electrostatic interactions among the C-terminal charged residues in random coils or in an alpha-helix.
Amino Acid Sequence ; Animals ; Dimerization ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Rabbits ; Recombinant Fusion Proteins/chemistry/genetics ; Ryanodine Receptor Calcium Release Channel/*chemistry/genetics ; Sequence Homology, Amino Acid ; Static Electricity

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Inhibition of gamma ray-induced apoptosis by stimulatory heterotrimeric GTP binding protein involves Bcl-xL down-regulation in SH-SY5Y human neuroblastoma cells.

So Young KIM ; Miran SEO ; Jung Min OH ; Eun Ah CHO ; Yong Sung JUHNN

Experimental & Molecular Medicine.2007;39(5):583-593.

Heterotrimeric GTP-binding proteins (G proteins) transduce extracellular signals into intracellular signals by activating effector molecules including adenylate cyclases that catalyze cAMP formation, and thus regulate various cellular responses such as metabolism, proliferation, and apoptosis. cAMP signaling pathways have been reported to protect cells from ionizing radiation-induced apoptosis, but however, the protective mechanism is not clear. Therefore, this study aimed to investigate the signaling molecules and the mechanism mediating the anti-apoptotic action of cAMP signaling system in radiation-induced apoptosis. Stable expression of a constitutively active mutant of G alpha s (G alpha sQL) protected gamma ray-induced apoptosis which was assessed by analysis of the cleavages of PARP, caspase-9, and caspase-3 and cytochrome C release in SH-SY5Y human neuroblastoma cells. G alpha sQL repressed the gamma ray-induced down-regulation of Bcl-xL protein, but transfection of Bcl-xL siRNA increased the gamma ray-induced apoptosis and abolished the anti-apoptotic effect of G alpha sQL. G alpha sQL decreased the degradation rate of Bcl-xL protein, and it also restrained the decrease in Bcl-xL mRNA by increasing the stability following ionizing irradiation. Furthermore, prostaglandin E2 that activates G alpha s was found to protect gamma ray-induced apoptosis, and the protective effect was abolished by treatment with prostanoid receptor antagonist specific to EP2/4R subtype. Moreover, specific agonists for adenosine A1 receptor that inhibits cAMP signaling pathway augmented gamma ray-induced apoptosis. From this study, it is concluded that Galphas-cAMP signaling system can protect SH-SY5Y cells from gamma ray-induced apoptosis partly by restraining down-regulation of Bcl-xL expression, suggesting that radiation-induced apoptosis can be modulated by GPCR ligands to improve the efficiency of radiation therapy.
Apoptosis/*physiology/*radiation effects ; Base Sequence ; Cell Line, Tumor ; Cyclic AMP/metabolism ; DNA Primers/genetics ; Down-Regulation/radiation effects ; GTP-Binding Protein alpha Subunits, Gs/*metabolism ; Gamma Rays ; Humans ; Neuroblastoma/genetics/metabolism/pathology ; RNA, Small Interfering/genetics ; Signal Transduction ; bcl-X Protein/genetics/*metabolism

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Calcium-influx increases SOD1 aggregates via nitric oxide in cultured motor neurons.

Hyun Jung KIM ; Wooseok IM ; Seungchan KIM ; Sung Hun KIM ; Jung Jun SUNG ; Manho KIM ; Kwang Woo LEE

Experimental & Molecular Medicine.2007;39(5):574-582.

Familial amyotrophic lateral sclerosis (fALS) is caused by mutations in Cu/Zn-superoxide dismutase (SOD1), and SOD1 aggregation and calcium toxicity are involved in neuronal death. However, the effect of altered calcium homeostasis on the SOD1 aggregation is unknown. To investigate whether calcium triggers mutant SOD1 aggregation in vitro, human mutant SOD1 (G93A) was transfected into motor neuronal cell line (VSC 4.1 cells). These cells were then treated with calcium ionophore A23187 or agents that induce intracellular calcium release like cyclic ADP ribose, ryanodine or thapsigargin. A23187 was found to increase mutant SOD1 aggregation and neuronal nitric oxide synthase (nNOS) expression. Moreover, the NOS inhibitor (L-NAME) and a NO-dependent cyclic GMP cascade inhibitor (ODQ) reduced SOD1 aggregation, whereas an exogenous NO donor (GSNO) increased mutant SOD1 aggregation, which was also prevented by NOS or cGMP cascade inhibitor. Our data demonstrate that calcium-influx increases SOD1 aggregation by upregulating NO in cultured motor neuronal cells.
Amyotrophic Lateral Sclerosis/genetics/metabolism ; Animals ; Calcimycin/pharmacology ; Calcium/*metabolism ; Calpain/metabolism ; Caspase 3/metabolism ; Cell Line ; Humans ; Ionophores/pharmacology ; Motor Neurons/*metabolism ; Multiprotein Complexes ; Mutation ; Nitric Oxide/*metabolism ; Rats ; Recombinant Proteins/chemistry/genetics/metabolism ; Superoxide Dismutase/chemistry/genetics/*metabolism ; Transfection

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WNKs: protein kinases with a unique kinase domain.

Chou Long HUANG ; Seung Kuy CHA ; Hao Ran WANG ; Jian XIE ; Melanie H COBB

Experimental & Molecular Medicine.2007;39(5):565-573.

WNKs (with-no-lysine [K]) are a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine relative to all other protein kinases. The roles of WNK kinases in regulating ion transport were first revealed by the findings that mutations of two members cause a genetic hypertension and hyperkalemia syndrome. More recent studies suggest that WNKs are pleiotropic protein kinases with important roles in many cell processes in addition to ion transport. Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development.
Amino Acid Sequence ; Animals ; Cell Proliferation ; Cell Survival ; Humans ; Hyperkalemia/enzymology/etiology/genetics ; Hypertension/enzymology/etiology/genetics ; Kidney/enzymology ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neoplasms/enzymology/etiology/genetics ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry/genetics/*metabolism ; Pseudohypoaldosteronism/enzymology/etiology/genetics ; Sequence Homology, Amino Acid ; Signal Transduction ; Syndrome

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Neural cell adhesion molecule (NCAM) promotes the differentiation of hippocampal precursor cells to a neuronal lineage, especially to a glutamatergic neural cell type.

Min Hwa SHIN ; Eu Gene LEE ; Sang Hun LEE ; Yong Sung LEE ; Hyeon SON

Experimental & Molecular Medicine.2002;34(6):401-410.

Rat hippocampal precursor cells isolated from hippocampi of embryonic day 16.5 (E16.5) rat embryos were found to proliferate in the presence of basic fibroblast growth factor. Addition of soluble neural cell adhesion molecule (NCAM) to these precursor cells reduced cell proliferation in a dose dependent manner and enhanced the induction of precursor cells' differentiation to the neuronal lineage. Given these findings that NCAM induces the differentiation of hippocampal precursor cells, we investigated possible effects of NCAM on the expression of basic helix-loop-helix (bHLH) transcription factors during the differentiation. Soluble NCAM upregulated the transcription of bHLH transcription factors, neurogenin1 and NeuroD, but decreased HES5. Western blot analysis showed that NCAM increased the expression levels of CaMKII, p-MAPK, GluR1 and NR1 but decreased p-STAT3. These results support a role for NCAM in the inhibition of proliferation and the induction of neural differentiation of hippocampal neural precursor cells, and act as developmental regulators of the bHLH families, ultimately leading to the generation of glutamatergic neural cell types in the differentiation of hippocampal precursor cells.
Animals ; Apoptosis/drug effects ; Cell Differentiation/*drug effects ; Cell Division/drug effects ; Cell Lineage/drug effects ; Cells, Cultured ; Helix-Loop-Helix Motifs ; Hippocampus/*cytology/*drug effects ; Neural Cell Adhesion Molecules/*pharmacology ; Neurons/cytology/*drug effects/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Receptors, Glutamate/*metabolism ; Signal Transduction ; Stem Cells/cytology/*drug effects ; Transcription Factors/genetics/metabolism

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Upregulation of extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases in human atherosclerosis infected with Chlamydia pneumoniae: The potential role of Chlamydia pneumoniae infection in the progression of atherosclerosis.

Eui Young CHOI ; Dong Soo KIM ; Bum Kee HONG ; Hyuck Moon KWON ; Young Goo SONG ; Ki Hyun BYUN ; Hyun Young PARK ; Ki Chul WHANG ; Hyun Seung KIM

Experimental & Molecular Medicine.2002;34(6):391-400.

Chlamydia pneumoniae infection implicated as an important etiologic factor of atherosclerosis, especially in coronary artery disease (CAD), was found in vitro to be associated with the induction of matrix metalloproteinases (MMPs). An extracellular matrix metalloproteinase inducer (EMMPRIN)/membrane-type 1 matrix metalloproteinase (MT1-MMP) system which induces and activates MMPs,is suggested to be functional and were upregulated in the failing myocardium. However, the upstream regulation of MMPs by C. pneumoniae within atheroma itself remains unclear. We evaluated the seroepidemiologic study of C. pneumoniae infection in CAD patients (n = 391) and controls (n = 97) and performed histopathological and in vitro analysis in atherosclerotic vascular tissues obtained from patients with seropositive to C. pneumoniae (n = 20), by using immunochemistry for C. pneumoniae, EMMPRIN/MT1-MMP, MMP-2, and MMP-9. The seropositive rates of both anti-C. pneumoniae IgG and IgA were 56.7% in CAD group and 43.3% in control group (P =0.033). Seropositive rate was increased in subgroups of CAD patients without conventional coronary risk factors compared to those with conventional risk factors. Immunoreactivities of EMMPRIN, MT1-MMP, MMP-2, and MMP-9 were increased in the atheromatous plaque itself, predominantly in immunoreactive macrophages/mononuclear cells to C. pneumoniae. Furthermore, Western blot analysis showed that EMMPRIN and MMP-2 were detected more prominently in atherosclerotic tissues infected with C. pneumoniae compared to control tissues. Zymographic analysis revealed that activities of MMP-2 and MMP-9 were more increased in atherosclerotic tissues infected with C. pneumoniae compared to control tissues. The present study demonstrated upstream regulation of MMPs can be induced by C. pneumoniae within atheromatous plaque itself. These findings help to understand the potential role of C. pneumoniae in the progression of atherosclerosis.
Aged ; Animals ; Arteriosclerosis/complications/enzymology/*microbiology/*pathology ; Blotting, Western ; Chlamydia Infections/*complications/enzymology/epidemiology/immunology ; Chlamydophila pneumoniae/immunology/*pathogenicity ; Disease Progression ; Extracellular Matrix/enzymology ; Female ; Gelatinases/*metabolism ; Human ; Immunohistochemistry ; Male ; Matrix Metalloproteinases/*metabolism ; Membrane Glycoproteins/*metabolism ; Middle Aged ; Up-Regulation

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Triptolide-induced suppression of phospholipase D expression inhibits proliferation of MDA-MB-231 breast cancer cells.

Dong Woo KANG ; Ji Young LEE ; Deuk hee OH ; Seon Yang PARK ; Tae Min WOO ; Mi Kyoung KIM ; Mi Hee PARK ; Young Hoon JANG ; Do Sik MIN

Experimental & Molecular Medicine.2009;41(9):678-685. doi:10.3858/emm.2009.41.9.074

In spite of the importance of phospholipase D (PLD) in cell proliferation and tumorigenesis, little is known about the molecules regulating PLD expression. Thus, identification of small molecules inhibiting PLD expression would be an important advance for PLD-mediated physiology. We examined one such here, denoted "Triptolide", which was identified in a chemical screen for inhibitors of PLD expression using cell assay system based on measurement of PLD promoter activity. Triptolide significantly suppressed the expression of both PLD1 and PLD2 with sub-microM potency in MDA-MB-231 breast cancer cells as analyzed by promoter assay and RT-PCR. Moreover, triptolide abolished the protein level of PLD in a time and dose-dependent manner. Triptolide-induced PLD1 downregulation was also observed in all the cancer cells examined, suggesting a general phenomenon detected in various cancer cells. Decrease of PLD expression by triptolide suppressed both basal and PMA-induced PLD activity. In addition, triptolide inhibited activation of NFkappaB which increased PLD1 expression. Ultimately, downregulation of PLD by triptolide inhibited proliferation of breast cancer cells. Taken together, we demonstrate that triptolide suppresses the expression of PLD via inhibition of NFkappaB activation and then decreases cell proliferation.
Antineoplastic Agents, Alkylating/*pharmacology ; Breast Neoplasms/drug therapy/enzymology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Diterpenes/*pharmacology ; Epoxy Compounds/pharmacology ; Female ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; NF-kappa B/genetics/metabolism ; Phenanthrenes/*pharmacology ; Phospholipase D/*genetics/metabolism

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B cell activation factor (BAFF) is a novel adipokine that links obesity and inflammation.

Yu Hee KIM ; Bong Hyuk CHOI ; Hyae Gyeong CHEON ; Myoung Sool DO

Experimental & Molecular Medicine.2009;41(3):208-216. doi:10.3858/emm.2009.41.3.024

B cell activation factor (BAFF) is a novel member of the TNF ligand superfamily, mainly produced by myeloid cells. BAFF has been shown to participate in B-cell survival and B- and T-cell maturation. BAFF expression in adipocytes has been recently demonstrated. In the current study, we verified that BAFF expression is increased during adipocyte differentiation. BAFF expression was augmented by TNF-alpha treatment and was decreased by rosiglitazone treatment. BAFF secretion in lean and in ob/ob mice sera were compared and smaller amount of BAFF was secreted in ob/ob mice. mRNA and protein expression were different between epididymal and visceral adipose tissue. BAFF expression was also increased in ob/ob mouse adipose tissue. We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation. However, the expression of TACI was distinct from that of BAFF-R and BCMA under TNF-alpha and BAFF ligand treatment. BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions, but TACI was reduced. Conversely, BAFF-R and BCMA expression levels were downregulated by rosiglitazone treatment, but TACI was increased. Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.
Adipocytes/cytology ; Adipokines/biosynthesis/*physiology ; Animals ; B-Cell Activating Factor/biosynthesis/*physiology ; B-Cell Activation Factor Receptor/metabolism ; Cell Differentiation ; Hypoglycemic Agents/pharmacology ; Inflammation/*metabolism ; Mice ; Obesity/*metabolism ; Thiazolidinediones/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology

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AMP kinase/cyclooxygenase-2 pathway regulates proliferation and apoptosis of cancer cells treated with quercetin.

Yun Kyoung LEE ; Song Yi PARK ; Young Min KIM ; Won Sup LEE ; Ock Jin PARK

Experimental & Molecular Medicine.2009;41(3):201-207. doi:10.3858/emm.2009.41.3.023

AMPK (AMP-activated protein kinase) is highly conserved in eukaryotes, where it functions primarily as a sensor of cellular energy status. Recent studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumor cells. In this study, quercetin activated AMPK in MCF breast cancer cell lines and HT-29 colon cancer cells, and this activation of AMPK seemed to be closely related to a decrease in COX-2 expression. The application of a COX-2 inhibitor or cox-2(-/-) cells supported the idea that AMPK is an upstream signal of COX-2, and is required for the anti-proliferatory and pro-apoptotic effects of quercetin. The suppressive or growth inhibitory effects of quercetin on COX-2 were abolished by treating cancer cells with an AMPK inhibitor Compound C. These results suggest that AMPK is crucial to the anti-cancer effect of quercetin and that the AMPK-COX-2 signaling pathway is important in quercetin-mediated cancer control.
AMP-Activated Protein Kinases/antagonists & inhibitors/*physiology ; Anticarcinogenic Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle/drug effects/physiology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cyclooxygenase 2/genetics/*physiology ; Cyclooxygenase 2 Inhibitors/pharmacology ; Enzyme Activation ; Humans ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Quercetin/*pharmacology

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