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Eeva Moilanen - One of the best experts on this subject based on the ideXlab platform.
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Aurothiomalate inhibits cyclooxygenase 2 matrix metalloproteinase 3 and interleukin 6 expression in chondrocytes by increasing mapk phosphatase 1 expression and decreasing p38 phosphorylation mapk phosphatase 1 as a novel target for antirheumatic dru
Arthritis & Rheumatism, 2010Co-Authors: Riina Nieminen, Riku Korhonen, Teemu Moilanen, Andrew R Clark, Eeva MoilanenAbstract:Objective Aurothiomalate is a disease-modifying antirheumatic drug that suppresses inflammation and retards cartilage degradation and bone erosion in arthritis. The molecular mechanisms of action of Aurothiomalate are not known in detail. MAPK pathways are major signaling pathways in inflammation that regulate the production of many inflammatory and destructive factors in arthritis. The purpose of the present study was to investigate the effects of Aurothiomalate on the activity of p38 MAPK and on the expression of MAPK phosphatase 1 (MKP-1), cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and interleukin-6 (IL-6) in immortalized murine H4 chondrocytes and in intact human and murine cartilage. Methods Protein expression was examined by Western blotting or by enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was examined by real-time reverse transcription–polymerase chain reaction analysis. The mediator role of MKP-1 was investigated by using small interfering RNA (siRNA) methods to down-regulated MKP-1 expression in chondrocytes in culture and by comparing the responses in intact cartilage from MKP-1–deficient and wild-type mice. The effects of Aurothiomalate were also confirmed in human rheumatoid cartilage by using tissue samples obtained at the time of total knee replacement surgery. Results Aurothiomalate inhibited IL-1β–induced COX-2 expression and prostaglandin E2 production by destabilizing COX-2 mRNA, as did the p38 MAPK inhibitor SB203580. Interestingly, Aurothiomalate also increased the expression of MKP-1 and reduced the IL-1β–induced phosphorylation of p38 MAPK. Knockdown of MKP-1 by siRNA significantly impaired the ability of Aurothiomalate to inhibit the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3, and IL-6. Likewise, Aurothiomalate reduced COX-2, MMP-3, and IL-6 expression in articular cartilage from patients with rheumatoid arthritis, as well as in articular cartilage from wild-type mice but not from MKP-1–/– mice. Conclusion Our findings indicate a novel mechanism for the antiinflammatory and antierosive actions of Aurothiomalate, through increased expression of MKP-1, which leads to reduced activation of p38 MAPK and suppressed expression of COX-2, MMP-3, and IL-6. The results suggest that manipulation of MKP-1 levels is a promising new mechanism to be directed in the search and development of novel antiinflammatory and antierosive compounds that have the good efficacy of gold compounds but not their toxicity.
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Aurothiomalate inhibits cox 2 expression in chondrocytes and in human cartilage possibly through its effects on cox 2 mrna stability
European Journal of Pharmacology, 2008Co-Authors: Riina Nieminen, Teemu Moilanen, Katriina Vuolteenaho, Asko Riutta, Hannu Kankaanranta, Peter M Van Der Kraan, Eeva MoilanenAbstract:Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, Aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of Aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because Aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in Aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, Aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with Aurothiomalate. The results show that Aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for Aurothiomalate which may be important in the treatment of arthritis.
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Aurothiomalate and hydroxychloroquine inhibit nitric oxide production in chondrocytes and in human osteoarthritic cartilage
Scandinavian Journal of Rheumatology, 2005Co-Authors: Katriina Vuolteenaho, Teemu Moilanen, P Kujala, Eeva MoilanenAbstract:Objectives: Nitric oxide (NO) is a destructive mediator produced by activated chondrocytes. The aim of the present study was to investigate the effect of disease‐modifying anti‐rheumatic drugs (DMARDs) on interleukin‐1β (IL‐1β)‐induced NO production in chondrocyte cultures, and in human osteoarthritic cartilage.Results: Aurothiomalate, hydroxychloroquine, methotrexate and leflunomide inhibited IL‐1β‐induced inducible NO synthase (iNOS) expression and NO production in immortalized H4 chondrocytes, while penicillamine and sulfasalazine had no effect. This can be explained by the fact that the four effective DMARDs also suppressed IL‐1β‐induced activation of nuclear factor kappa B (NF‐κB), which is a crucial transcription factor for iNOS. Aurothiomalate and hydroxychloroquine also inhibited IL‐1β‐induced NO production in OA cartilage whereas methotrexate and leflunomide had no effect.Conclusion: Aurothiomalate and hydroxychloroquine suppressed IL‐1β‐induced NO production in chondrocyte cultures and in OA car...
Riina Nieminen - One of the best experts on this subject based on the ideXlab platform.
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Aurothiomalate inhibits cyclooxygenase 2 matrix metalloproteinase 3 and interleukin 6 expression in chondrocytes by increasing mapk phosphatase 1 expression and decreasing p38 phosphorylation mapk phosphatase 1 as a novel target for antirheumatic dru
Arthritis & Rheumatism, 2010Co-Authors: Riina Nieminen, Riku Korhonen, Teemu Moilanen, Andrew R Clark, Eeva MoilanenAbstract:Objective Aurothiomalate is a disease-modifying antirheumatic drug that suppresses inflammation and retards cartilage degradation and bone erosion in arthritis. The molecular mechanisms of action of Aurothiomalate are not known in detail. MAPK pathways are major signaling pathways in inflammation that regulate the production of many inflammatory and destructive factors in arthritis. The purpose of the present study was to investigate the effects of Aurothiomalate on the activity of p38 MAPK and on the expression of MAPK phosphatase 1 (MKP-1), cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and interleukin-6 (IL-6) in immortalized murine H4 chondrocytes and in intact human and murine cartilage. Methods Protein expression was examined by Western blotting or by enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was examined by real-time reverse transcription–polymerase chain reaction analysis. The mediator role of MKP-1 was investigated by using small interfering RNA (siRNA) methods to down-regulated MKP-1 expression in chondrocytes in culture and by comparing the responses in intact cartilage from MKP-1–deficient and wild-type mice. The effects of Aurothiomalate were also confirmed in human rheumatoid cartilage by using tissue samples obtained at the time of total knee replacement surgery. Results Aurothiomalate inhibited IL-1β–induced COX-2 expression and prostaglandin E2 production by destabilizing COX-2 mRNA, as did the p38 MAPK inhibitor SB203580. Interestingly, Aurothiomalate also increased the expression of MKP-1 and reduced the IL-1β–induced phosphorylation of p38 MAPK. Knockdown of MKP-1 by siRNA significantly impaired the ability of Aurothiomalate to inhibit the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3, and IL-6. Likewise, Aurothiomalate reduced COX-2, MMP-3, and IL-6 expression in articular cartilage from patients with rheumatoid arthritis, as well as in articular cartilage from wild-type mice but not from MKP-1–/– mice. Conclusion Our findings indicate a novel mechanism for the antiinflammatory and antierosive actions of Aurothiomalate, through increased expression of MKP-1, which leads to reduced activation of p38 MAPK and suppressed expression of COX-2, MMP-3, and IL-6. The results suggest that manipulation of MKP-1 levels is a promising new mechanism to be directed in the search and development of novel antiinflammatory and antierosive compounds that have the good efficacy of gold compounds but not their toxicity.
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Aurothiomalate inhibits cox 2 expression in chondrocytes and in human cartilage possibly through its effects on cox 2 mrna stability
European Journal of Pharmacology, 2008Co-Authors: Riina Nieminen, Teemu Moilanen, Katriina Vuolteenaho, Asko Riutta, Hannu Kankaanranta, Peter M Van Der Kraan, Eeva MoilanenAbstract:Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, Aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of Aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because Aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in Aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, Aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with Aurothiomalate. The results show that Aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for Aurothiomalate which may be important in the treatment of arthritis.
Teemu Moilanen - One of the best experts on this subject based on the ideXlab platform.
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Aurothiomalate inhibits cyclooxygenase 2 matrix metalloproteinase 3 and interleukin 6 expression in chondrocytes by increasing mapk phosphatase 1 expression and decreasing p38 phosphorylation mapk phosphatase 1 as a novel target for antirheumatic dru
Arthritis & Rheumatism, 2010Co-Authors: Riina Nieminen, Riku Korhonen, Teemu Moilanen, Andrew R Clark, Eeva MoilanenAbstract:Objective Aurothiomalate is a disease-modifying antirheumatic drug that suppresses inflammation and retards cartilage degradation and bone erosion in arthritis. The molecular mechanisms of action of Aurothiomalate are not known in detail. MAPK pathways are major signaling pathways in inflammation that regulate the production of many inflammatory and destructive factors in arthritis. The purpose of the present study was to investigate the effects of Aurothiomalate on the activity of p38 MAPK and on the expression of MAPK phosphatase 1 (MKP-1), cyclooxygenase 2 (COX-2), matrix metalloproteinase 3 (MMP-3), and interleukin-6 (IL-6) in immortalized murine H4 chondrocytes and in intact human and murine cartilage. Methods Protein expression was examined by Western blotting or by enzyme-linked immunosorbent assay, and messenger RNA (mRNA) expression was examined by real-time reverse transcription–polymerase chain reaction analysis. The mediator role of MKP-1 was investigated by using small interfering RNA (siRNA) methods to down-regulated MKP-1 expression in chondrocytes in culture and by comparing the responses in intact cartilage from MKP-1–deficient and wild-type mice. The effects of Aurothiomalate were also confirmed in human rheumatoid cartilage by using tissue samples obtained at the time of total knee replacement surgery. Results Aurothiomalate inhibited IL-1β–induced COX-2 expression and prostaglandin E2 production by destabilizing COX-2 mRNA, as did the p38 MAPK inhibitor SB203580. Interestingly, Aurothiomalate also increased the expression of MKP-1 and reduced the IL-1β–induced phosphorylation of p38 MAPK. Knockdown of MKP-1 by siRNA significantly impaired the ability of Aurothiomalate to inhibit the phosphorylation of p38 MAPK and the expression of COX-2, MMP-3, and IL-6. Likewise, Aurothiomalate reduced COX-2, MMP-3, and IL-6 expression in articular cartilage from patients with rheumatoid arthritis, as well as in articular cartilage from wild-type mice but not from MKP-1–/– mice. Conclusion Our findings indicate a novel mechanism for the antiinflammatory and antierosive actions of Aurothiomalate, through increased expression of MKP-1, which leads to reduced activation of p38 MAPK and suppressed expression of COX-2, MMP-3, and IL-6. The results suggest that manipulation of MKP-1 levels is a promising new mechanism to be directed in the search and development of novel antiinflammatory and antierosive compounds that have the good efficacy of gold compounds but not their toxicity.
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Aurothiomalate inhibits cox 2 expression in chondrocytes and in human cartilage possibly through its effects on cox 2 mrna stability
European Journal of Pharmacology, 2008Co-Authors: Riina Nieminen, Teemu Moilanen, Katriina Vuolteenaho, Asko Riutta, Hannu Kankaanranta, Peter M Van Der Kraan, Eeva MoilanenAbstract:Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, Aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of Aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because Aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in Aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, Aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with Aurothiomalate. The results show that Aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for Aurothiomalate which may be important in the treatment of arthritis.
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Aurothiomalate and hydroxychloroquine inhibit nitric oxide production in chondrocytes and in human osteoarthritic cartilage
Scandinavian Journal of Rheumatology, 2005Co-Authors: Katriina Vuolteenaho, Teemu Moilanen, P Kujala, Eeva MoilanenAbstract:Objectives: Nitric oxide (NO) is a destructive mediator produced by activated chondrocytes. The aim of the present study was to investigate the effect of disease‐modifying anti‐rheumatic drugs (DMARDs) on interleukin‐1β (IL‐1β)‐induced NO production in chondrocyte cultures, and in human osteoarthritic cartilage.Results: Aurothiomalate, hydroxychloroquine, methotrexate and leflunomide inhibited IL‐1β‐induced inducible NO synthase (iNOS) expression and NO production in immortalized H4 chondrocytes, while penicillamine and sulfasalazine had no effect. This can be explained by the fact that the four effective DMARDs also suppressed IL‐1β‐induced activation of nuclear factor kappa B (NF‐κB), which is a crucial transcription factor for iNOS. Aurothiomalate and hydroxychloroquine also inhibited IL‐1β‐induced NO production in OA cartilage whereas methotrexate and leflunomide had no effect.Conclusion: Aurothiomalate and hydroxychloroquine suppressed IL‐1β‐induced NO production in chondrocyte cultures and in OA car...
Isao Makino - One of the best experts on this subject based on the ideXlab platform.
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zinc ions antagonize the inhibitory effect of Aurothiomalate on glucocorticoid receptor function at physiological concentrations
Molecular Pharmacology, 1995Co-Authors: Hirotoshi Tanaka, Y Makino, K D Wright, Janake Gustafsson, Kensaku Okamoto, Isao MakinoAbstract:The water-soluble gold preparation Aurothiomalate, which contains gold as Au(I), is frequently prescribed for patients with rheumatoid arthritis as a disease-modifying agent. We report that Aurothiomalate negatively modulates glucocorticoid hormone action; it represses the ligand- and DNA-binding activities and the transactivation function of the glucocorticoid receptor. We suggested the existence of endogenous titrating activities of Au(I) because otherwise administration of Aurothiomalate to a patient with rheumatoid arthritis would be expected to result in peripheral insensitivity to glucocorticoids and worsen the patient's status. Focusing on metal ions that are present in vivo, we found that Zn(II) counteracts the inhibitory effect of Au(I) on glucocorticoid receptor function. This complementary effect of Zn(II) was observed at physiological concentrations. We suggest that Zn(II) preserves glucocorticoid receptor function in target tissues and maintains hormone responsiveness, even with chrysotherapy.
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repression of glucocorticoid receptor function by the anti rheumatic gold compound Aurothiomalate
Biochemical and Biophysical Research Communications, 1993Co-Authors: Yuichi Makino, Hirotoshi Tanaka, Fuminori Hirano, Etsushi Fukawa, Isao MakinoAbstract:We describe functional interaction between the anti-rheumatic water-soluble gold compound Aurothiomalate and glucocorticoid receptors. Aurothiomalate contains gold in the Au(I) state, and Au(I) alone, not thiomalate or malate, reduced the ligand-binding activity of the glucocorticoid receptor. Au(I) also interfered with the productive interaction between the glucocorticoid receptor and the cognate target DNA sequences and repressed the transactivation function of the receptor. Thus, Au(I) variably modulates glucocorticoid receptor-mediated intracellular signals.
Alan P Fields - One of the best experts on this subject based on the ideXlab platform.
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a small molecule inhibitor of atypical protein kinase c signaling inhibits pancreatic cancer cell transformed growth and invasion
Oncotarget, 2015Co-Authors: Amanda M Butler, Alan P Fields, Michele Scotti L Buzhardt, Eda Erdogan, Shuhua Li, Kristin S Inman, Nicole R MurrayAbstract:// Amanda M. Butler 1 , Michele L. Scotti Buzhardt 2 , Eda Erdogan 3 , Shuhua Li 1 , Kristin S. Inman 1 , Alan P. Fields 1 and Nicole R. Murray 1 1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA 2 Genoptix/Novartis Molecular Diagnostics, Carlsbad, CA, USA 3 Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA Correspondence to: Nicole R. Murray, email: // Keywords : atypical PKCs, Aurothiomalate, pancreatic cancer, transformed growth, invasion Received : July 30, 2014 Accepted : March 10, 2015 Published : April 14, 2015 Abstract Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, Aurothiomalate, also disrupts PKCζ/Par6 interaction; 3) Aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro ; and 4) Aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo . Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.
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phase i dose escalation study of the protein kinase c iota inhibitor Aurothiomalate for advanced non small cell lung cancer ovarian cancer and pancreatic cancer
Journal of Clinical Oncology, 2013Co-Authors: Aaron S Mansfield, Alan P Fields, Aminah Jatoi, Alex A Adjei, Charles Erlichman, Julian R MolinaAbstract:2551 Background: Protein kinase C iota (PKCi) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers and promotes tumorigenesis. The gold compound Aurothiomalate (ATM) inhi...
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PKCι regulates K-rasG12D-induced ADM.
2012Co-Authors: Michele L. Scotti, Michael Leitges, Alan P Fields, Amanda M Butler, Kristin E. Smith, Shelly R. Calcagno, Howard C. Crawford, Nicole R MurrayAbstract:A, B) Pancreatic acinar cells from LSL-Kras and LSL-Kras;Prkcif/f mice were incubated with Ad-null or Ad-Cre and embedded in collagen. Cultures were A) photographed on day 7 (Scale bar, 200 µm) and B) quantified for metaplastic duct formation. C) Pancreatic acinar cells from P48-Cre;LSL-Kras mice were embedded in collagen ± 100 µM Aurothiomalate (ATM). B, C) Quantitative analysis of metaplastic duct formation is plotted. Plots are the average of three independent experiments. Bars = mean ± SEM and *P
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atypical protein kinase cι is required for bronchioalveolar stem cell expansion and lung tumorigenesis
Cancer Research, 2009Co-Authors: Roderick P Regala, Rebecca K Davis, Alyssa Kunz, Andras Khoor, Michael Leitges, Alan P FieldsAbstract:Protein kinase Ciota (PKCiota) is an oncogene required for maintenance of the transformed phenotype of non-small cell lung cancer cells. However, the role of PKCiota in lung tumor development has not been investigated. To address this question, we established a mouse model in which oncogenic Kras(G12D) is activated by Cre-mediated recombination in the lung with or without simultaneous genetic loss of the mouse PKCiota gene, Prkci. Genetic loss of Prkci dramatically inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. This effect correlates with a defect in the ability of Prkci-deficient bronchioalveolar stem cells to undergo Kras-mediated expansion and morphologic transformation in vitro and in vivo. Furthermore, the small molecule PKCiota inhibitor Aurothiomalate inhibits Kras-mediated bronchioalveolar stem cell expansion and lung tumor growth in vivo. Thus, Prkci is required for oncogene-induced expansion and transformation of tumor-initiating lung stem cells. Furthermore, Aurothiomalate is an effective antitumor agent that targets the tumor-initiating stem cell niche in vivo. These data have important implications for PKCiota as a therapeutic target and for the clinical use of Aurothiomalate for lung cancer treatment.
