Osteoarthritis (OA), the most common form of joint disease, is characterized clinically by joint pain, stiffness,and deformity. OA is now considered a whole joint disease;however, the breakdown of the articular cartil...Osteoarthritis (OA), the most common form of joint disease, is characterized clinically by joint pain, stiffness,and deformity. OA is now considered a whole joint disease;however, the breakdown of the articular cartilage remains themajor hallmark of the disease. Current treatments targeting OA symptoms have a limited impact on impeding orreversing the OA progression. Understanding the molecular and cellular mechanisms underlying OA development isa critical barrier to progress in OA therapy. Recent studies by the current authors’ group and others have revealedthat the nuclear factor of activated T cell 1 (NFAT1), a member of the NFAT family of transcription factors, regulatesthe expression of many anabolic and catabolic genes in articular chondrocytes of adult mice. Mice lacking NFAT1exhibit normal skeletal development but display OA in both appendicular and spinal facet joints as adults. Thisreview mainly focuses on the recent advances in the regulatory role of NFAT1 transcription factor in the activities ofarticular chondrocytes and its implication in the pathogenesis of OA.展开更多
There is an increasing interest in development of novel anticancer agents that target oncogenes.We have recently discovered that nuclear factor of activated T cells 1(NFAT1) is a novel regulator of the Mouse Double Mi...There is an increasing interest in development of novel anticancer agents that target oncogenes.We have recently discovered that nuclear factor of activated T cells 1(NFAT1) is a novel regulator of the Mouse Double Minute 2(MDM2) oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and progression,justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and development of novel cancer therapeutics.The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A(LinA),a novel natural product inhibitor of the NFAT1-MDM2 pathway.The cytotoxicity of LinA was first tested in various human cancer cell lines in comparison with normal cell lines.The results showed that the breast cancer cells were highly sensitive to LinA treatment.We next demonstrated the effects of LinA on cell proliferation,colony formation,cell cycle progression,and apoptosis in breast cancer MCF7 and MDA-MB-231 cells,in dose-dependent and p53-independent manners.LinA also inhibited the migration and invasion of these cancer cells.Our mechanistic studies further indicated that its anticancer activities were attributed to its inhibitory effects on the NFAT1-MDM2 pathway and modulatory effects on the expression of key proteins involved in cell cycle progression,apoptosis,and DNA damage.In summary,LinA is a novel NFAT1-MDM2 inhibitor and may be developed as a preventive and therapeutic agent against human cancer.展开更多
基金supported by the United States National Institutes of Health(NIH)under Award Number R01 AR059088(to J.W.)the Mary A.and Paul R.Harrington Distinguished Professorship Endowment.
文摘Osteoarthritis (OA), the most common form of joint disease, is characterized clinically by joint pain, stiffness,and deformity. OA is now considered a whole joint disease;however, the breakdown of the articular cartilage remains themajor hallmark of the disease. Current treatments targeting OA symptoms have a limited impact on impeding orreversing the OA progression. Understanding the molecular and cellular mechanisms underlying OA development isa critical barrier to progress in OA therapy. Recent studies by the current authors’ group and others have revealedthat the nuclear factor of activated T cell 1 (NFAT1), a member of the NFAT family of transcription factors, regulatesthe expression of many anabolic and catabolic genes in articular chondrocytes of adult mice. Mice lacking NFAT1exhibit normal skeletal development but display OA in both appendicular and spinal facet joints as adults. Thisreview mainly focuses on the recent advances in the regulatory role of NFAT1 transcription factor in the activities ofarticular chondrocytes and its implication in the pathogenesis of OA.
基金supported by the National Institutes of Health(NIH) grant R01 CA186662(to R.Z.) and CA102514(to R.A.)supported by American Cancer Society(ACS) grant RSG-15-009-01-CDD (to W.W.)
文摘There is an increasing interest in development of novel anticancer agents that target oncogenes.We have recently discovered that nuclear factor of activated T cells 1(NFAT1) is a novel regulator of the Mouse Double Minute 2(MDM2) oncogene and the NFAT1-MDM2 pathway has been implicated in human cancer development and progression,justifying that targeting the NFAT1-MDM2 pathway could be a novel strategy for discovery and development of novel cancer therapeutics.The present study was designed to examine the anticancer activity and underlying mechanisms of action of lineariifolianoid A(LinA),a novel natural product inhibitor of the NFAT1-MDM2 pathway.The cytotoxicity of LinA was first tested in various human cancer cell lines in comparison with normal cell lines.The results showed that the breast cancer cells were highly sensitive to LinA treatment.We next demonstrated the effects of LinA on cell proliferation,colony formation,cell cycle progression,and apoptosis in breast cancer MCF7 and MDA-MB-231 cells,in dose-dependent and p53-independent manners.LinA also inhibited the migration and invasion of these cancer cells.Our mechanistic studies further indicated that its anticancer activities were attributed to its inhibitory effects on the NFAT1-MDM2 pathway and modulatory effects on the expression of key proteins involved in cell cycle progression,apoptosis,and DNA damage.In summary,LinA is a novel NFAT1-MDM2 inhibitor and may be developed as a preventive and therapeutic agent against human cancer.
