Showing papers by "Michael Karin published in 2010"

Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression

Abstract: T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their impact on tumor progression is poorly understood. Targeted deletion of the hypoxia responsive transcription factor HIF-1α in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although VEGF-A and vascularization was unchanged. Tumor associated macrophages can suppress tumor infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T cell suppression in the tumor microenvironment.

Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies

Abstract: Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.

B-cell-derived lymphotoxin promotes castration-resistant prostate cancer

Abstract: Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12-18 months. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-kappaB activation supports its growth. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IkappaB kinase (IKK)-beta and its target NF-kappaB have important tumour-promoting functions within malignant cells and inflammatory cells. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-alpha, which stimulates metastasis by an NF-kappaB-independent, cell autonomous mechanism. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-beta activation results in production of cytokines that activate IKK-alpha and STAT3 in CaP cells to enhance hormone-free survival.

Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines

Abstract: Balanced production of type I interferons and proinflammatory cytokines after engagement of Toll-like receptors (TLRs), which signal through adaptors containing a Toll-interleukin 1 receptor (TIR) domain, such as MyD88 and TRIF, has been proposed to control the pathogenesis of autoimmune disease and tumor responses to inflammation. Here we show that TRAF3, a ubiquitin ligase that interacts with both MyD88 and TRIF, regulated the production of interferon and proinflammatory cytokines in different ways. Degradative ubiquitination of TRAF3 during MyD88-dependent TLR signaling was essential for the activation of mitogen-activated protein kinases (MAPKs) and production of inflammatory cytokines. In contrast, TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response. Inhibition of degradative ubiquitination of TRAF3 prevented the expression of all proinflammatory cytokines without affecting the interferon response.

JNK1 and IKKβ: molecular links between obesity and metabolic dysfunction

Abstract: Inflammation is thought to underlie the pathogenesis of many chronic diseases. It is now established that obesity results in a state of chronic low-grade inflammation thought to contribute to several metabolic disorders, including insulin resistance and pancreatic islet dysfunction. The protein kinases JNK1 and IKKbeta have been found to serve as critical molecular links between obesity, metabolic inflammation, and disorders of glucose homeostasis. The precise mechanisms of these linkages are still being investigated. However, as we discuss here, JNK1 and IKKbeta are activated by almost all forms of metabolic stress that have been implicated in insulin resistance or islet dysfunction. Furthermore, both JNK1 and IKKbeta are critically involved in the promotion of diet-induced obesity, metabolic inflammation, insulin resistance, and beta-cell dysfunction. Understanding the molecular mechanisms by which JNK1 and IKKbeta mediate obesity-induced metabolic stress is likely to be of importance for the development of new treatments for a variety of obesity-associated diseases.

Cancer and inflammation: Promise for biologic therapy

Abstract: Cancers often arise as the end stage of inflammation in adults, but not in children. As such there is a complex interplay between host immune cells during neoplastic development, with both an ability to promote cancer as well as limit or eliminate it, most often complicit with the host. In humans, defining inflammation and the presence of inflammatory cells within or surrounding the tumor is a critical aspect of modern pathology. Groups defining staging for neoplasms are strongly encouraged to assess and incorporate measures of the presence of apoptosis, autophagy, and necrosis as well as the nature and quality of the immune infiltrate. Both environmental as well as genetic factors enhance the risk of cigarette smoking, H. pylori, hepatitis B/C, human papilloma virus, solar irradiation, asbestos, pancreatitis, or other causes of chronic inflammation. Identifying suitable genetic polymorphisms in cytokines, cytokine receptors, and Toll-like receptors among other immune response genes is also seen as high value as genomic sequencing becomes less expensive. Animal models which incorporate and assess not only the genetic anlagen but also the inflammatory cells and the presence of microbial pathogen [PAMPs] and damage associated molecular pattern molecules [DAMPs] are necessary. Identifying micro-RNAs involved in regulating the response to damage or injury are seen as highly promising. Although no therapeutic strategies to prevent or treat cancers based on insights into inflammatory pathways are currently approved for the common epithelial malignancies, there remains substantial interest in agents targeting COX2 or PPARγ, ethyl pyruvate, as well as steroids and several novel agents on the horizon.

Stressin' Sestrins take an aging fight

Abstract: Sestrins (Sesns) are a family of highly conserved stress-responsive proteins, transcriptionally regulated by p53 and forkhead transcription factor that exhibit oxidoreductase activity in vitro and can protect cells from oxidative stress. However, their major biochemical and physiological function does not appear to depend on their redox (reduction and oxidation) activity. Sesns promote activation of adenosine-5′-monophosphate (AMP)-dependent protein kinase in both mammals and flies. Stress-induced Sesn expression results in inhibition of the target of rapamycin complex 1 (TORC1) and the physiological and pathological implications of disrupting the Sesns-TORC1 crosstalk are now being unravelled. Detailing their mechanism of action and exploring their roles in human physiology point to exciting new insights to topics as diverse as stress, cancer, metabolism and aging.

Magnetically vectored nanocapsules for tumor penetration and remotely switchable on-demand drug release.

Abstract: Nanocapsules containing intentionally trapped magnetic nanoparticles and defined anticancer drugs have been prepared to provide a powerful magnetic vector under moderate gradient magnetic fields. These nanocapsules can penetrate into the interior of tumors and allow a controlled on-off switchable release of the drug cargo via remote RF field. This smart drug delivery system is compact as all the components can be self-contained in 80-150 nm capsules. In vitro as well as in vivo results indicate that these nanocapsules can be enriched near the mouse breast tumor and are effective in reducing tumor cell growth.

Conditional ablation of Ikkb inhibits melanoma tumor development in mice

Abstract: Several lines of evidence suggest that tumor cells show elevated activity of the NF-kappaB transcription factor, a phenomenon often resulting from constitutive activity of IkappaB kinase beta (IKKbeta). However, others have found that loss of NF-kappaB activity or IKKbeta is tumor promoting. The role of NF-kappaB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKbeta in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby HRasV12 is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkb were protected from HRasV12-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkbeta-mediated NF-kappaB activity.

B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia.

Abstract: Mice bearing a v-Myc myelocytomatosis viral oncogene homolog (c-Myc) transgene controlled by an Ig-alpha heavy-chain enhancer (iMycCα mice) rarely develop lymphomas but instead have increased rates of memory B-cell turnover and impaired antibody responses to antigen. We found that male progeny of iMycCα mice mated with mice transgenic (Tg) for CD257 (B-cell activating factor, BAFF) developed CD5+ B-cell leukemia resembling human chronic lymphocytic leukemia (CLL), which also displays a male gender bias. Surprisingly, leukemic cells of Myc/Baff Tg mice expressed higher levels of c-Myc than did B cells of iMycCα mice. We found that CLL cells of many patients with progressive disease also expressed high amounts of c-MYC, particularly CLL cells whose survival depends on nurse-like cells (NLC), which express high-levels of BAFF. We find that BAFF could enhance CLL-cell expression of c-MYC via activation the canonical IκB kinase (IKK)/NF-κB pathway. Inhibition of the IKK/NF-κB pathway in mouse or human leukemia cells blocked the capacity of BAFF to induce c-MYC or promote leukemia-cell survival and significantly impaired disease progression in Myc/Baff Tg mice. This study reveals an important relationship between BAFF and c-MYC in CLL which may affect disease development and progression, and suggests that inhibitors of the canonical NF-κB pathway may be effective in treatment of patients with this disease.

Sestrins at the crossroad between stress and aging.

Abstract: Sestrins are a family of stress-inducible proteins that can function as antioxidants and as inhibitors of target of rapamycin complex 1. In this research perspective, we discuss the possible roles of Sestrins in diverse stress-induced patho-physiological contexts that can result in premature aging and age-related diseases. We suggest that Sestrins provide critical feedback regulation that adjust metabolic and stress responses to different environmental cues and evolutionary constraints.

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1β after stimulation via Fcγ receptors (FcγRs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and FcγR-triggered IL-1β production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.

Sphingolipids: The Oil on the TRAFire That Promotes Inflammation

Abstract: Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) control inflammatory and immune responses by acting downstream of TNFRs and Toll-like receptors (TLRs) TRAF2 in particular has been extensively studied for its involvement in signaling by TNF-α, the classic inflammatory cytokine Because it has a RING finger, it has been suggested that TRAF2 acts as an E3 ubiquitin ligase that catalyzes the noncanonical Lys-63 (K63)-linked polyubiquitination of receptor-induced protein 1 (RIP1), which is an essential event in the activation of the IκB kinase complex and consequently nuclear factor κB Furthermore, TRAF2 itself is subject to K63-linked polyubiquitination, a modification that is rapidly induced upon receptor ligation and was interpreted to be the result of self-ubiquitination However, formal evidence that TRAF2 is an active E3 ubiquitin ligase was lacking New evidence shows that sphingosine-1-phosphate (S1P), a sphingolipid that is synthesized during inflammatory responses, is an essential cofactor for TRAF2 ubiquitin ligase activity S1P binds to TRAF2 and promotes TRAF2-mediated K63-linked RIP1 polyubiquitination, providing direct evidence that TRAF2 is an active E3 ubiquitin ligase and also introducing lipid second messengers into the realm of TNFR and TLR signaling

NF-kB : a network hub controlling immunity, inflammation, and cancer : a subject collection from Cold Spring Harbor perspectives in biology

Abstract: NF-kB is a critical signaling molecule in the immune system that regulates cell survival and cell death, lymphocyte responses, and inflammation. Acting as a transcription factor that can receive several inputs, it coordinates distinct gene expression programs in response to a wide variety of stimuli. Written and edited by experts in the field, this volume includes contributions covering the structure of NF-kB, its DNA-binding activity and specificity, the role of the inhibitor I-?B, and canonical and alternative mechanisms of NF-kB activation. The contributors examine the physiological role of NF-kB in immune cells, as well as its functions in other tissues, such as the nervous system. They also discuss work indicating that NF-kB represents a critical link between inflammation and cancer. Including clinical perspectives on the use of NF-kB inhibitors in cancer therapy and a historical introduction by David Baltimore, in whose lab NF-kB was discovered, this volume is a vital reference for cell and molecular biologists, immunologists, and pathologists interested in regulation of cell function.