Antonio De la Vieja

The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer

The activating mutation BRAF(V600E) is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)beta loop. BRAF induces secretion of functional TGFbeta and blocking TGFbeta/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFbeta cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFbeta and other key components of TGFbeta signaling, such as TbetaRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFbeta. Moreover, this high TGFbeta/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFbeta is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFbeta and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFbeta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression.

Glucose-Induced β-Catenin Acetylation Enhances Wnt Signaling in Cancer

Nuclear accumulation of β-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of β-catenin in response to Wnt signaling. Glucose-dependent β-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger β-catenin acetylation. Consequently β-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/β-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.

A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose

Extensive epidemiological studies suggest that the diabetic population is at higher risk of site-specific cancers. The diabetes-cancer link has been hypothesized to rely on various hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic (hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation may have an important but incompletely understood role. As a growth factor, insulin directly, or indirectly through IGF1, has been considered the major link between diabetes and cancer, while high glucose has been considered as a subordinate cause. Here we discuss the evidence that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which hyperglycemia may enhance the appearance, growth and survival of diabetes-associated cancers. High glucose triggers several direct and indirect mechanisms that cooperate to promote cancer cell proliferation, migration, invasion and immunological escape. In particular, high glucose enhancement of WNT/β-catenin signaling in cancer cells promotes proliferation, survival and senescence bypass, and represents a previously unrecognized direct mechanism linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of tumor cells and may ensure enhanced WNT signaling for continuous proliferation. Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase and decreased sirtuin 1 deacetylase activity, leading to β-catenin acetylation at lysine K354, a requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The impact of high glucose on β-catenin illustrates the remodeling of cancer-associated signaling pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive much research attention in the coming years. Future epidemiological studies may be guided and complemented by the identification of these metabolic interplays. Together, these studies should lead to the development of new preventive strategies for diabetes-associated cancers.

From obesity to diabetes and cancer: epidemiological links and role of therapies

Increasing evidence suggests a complex relationship between obesity, diabetes and cancer. Here we review the evidence for the association between obesity and diabetes and a wide range of cancer types. In many cases the evidence for a positive association is strong, but for other cancer types a more complex picture emerges with some site-specific cancers associated with obesity but not to diabetes, and some associated with type I but not type II diabetes. The evidence therefore suggests the existence of cumulative common and differential mechanisms influencing the relationship between these diseases. Importantly, we highlight the influence of antidiabetics on cancer and antineoplastic agents on diabetes and in particular that antineoplastic targeting of insulin/IGF-1 signalling induces hyperglycaemia that often evolves to overt diabetes. Overall, a coincidence of diabetes and cancer worsens outcome and increases mortality. Future epidemiology should consider dose and time of exposure to both disease and treatment, and should classify cancers by their molecular signatures. Well-controlled studies on the development of diabetes upon cancer treatment are necessary and should identify the underlying mechanisms responsible for these reciprocal interactions. Given the global epidemic of diabetes, preventing both cancer occurrence in diabetics and the onset of diabetes in cancer patients will translate into a substantial socioeconomic benefit.

Regulation of thyroid oxidative state by thioredoxin reductase has a crucial role in thyroid responses to iodide excess.

The phenomenon that supraphysiological doses of iodide (I(-)) temporarily inhibit thyroid hormone synthesis is known as thyroid iodide autoregulation. Recovery of thyroid function has been attributed to sodium-iodide symporter (NIS) inhibition, but the diversity of available data makes it difficult to reach definitive conclusions. Iodide excess induces reactive oxygen species production and cell toxicity. However, the roles of the oxidative state of the cell and antioxidant selenoproteins in I(-) autoregulation have never been explored. Here we analyze the effects of high I(-) doses in rat thyroids and in PCCl3 cells in the period comprising I(-) autoregulation (i.e. 0-72 h after I(-) administration), focusing on NIS expression, redox state, and the expression and activity of selenoproteins. Our results show that NIS mRNA inhibition by I(-) does not occur at the transcriptional level, because neither NIS promoter activity nor Pax8 expression or its binding to DNA was modulated. Because I(-) uptake was inhibited much earlier than NIS protein, and no effect was observed on its subcellular localization, we suggest that I(-) is inhibiting NIS in the plasma membrane. The increased reactive oxygen species production leads to an increase in thioredoxin reductase mRNA levels and enzyme activity, which reduces the oxidative stress. Inhibition of thioredoxin reductase at either gene expression or activity levels prevented NIS recovery, thus illustrating a new role played by this selenoprotein in the regulation of cell homeostasis and consequently in I(-) autoregulation.

Telomerase-driven expression of the sodium iodide symporter (NIS) for in vivo radioiodide treatment of cancer: A new broad-spectrum NIS-mediated antitumor approach

CONTEXT Telomerase promoters (hTERT and hTR) are useful for transcriptional targeting in gene therapy models of cancer. Telomerase-driven expression of the sodium iodide symporter (NIS) in tumor cells has been successfully used as a reporter gene in vivo using positron emission tomography (PET) imaging. OBJECTIVE The aim of this study was to investigate the NIS-mediated therapeutic effect of telomerase promoters in a wide variety of human cancer cell lines. DESIGN AND METHODS Promoter fragments from either hTERT or hTR were used to drive the expression of NIS in cell lines derived from melanoma (M14), breast (MDA-MB-231), colon (HT-29), lung (H460), ovarian (OVCAR-3), and thyroid (TPC-1) carcinomas. Iodide uptake assays, protein immunodetection, and clonigenic assays were used to confirm NIS functional expression and the (131)I-mediated cytopathic effect. Tumor xenografts in mice were infected with hTERT and hTR and then treated using radioiodide. RESULTS Both promoters were selectively active in cancer cells that were effectively killed by exposure to (131)I. One single dose of 1 mCi (131)I markedly suppressed tumor growth of melanoma-derived tumor xenografts compared with controls. This effect was more modest in colon cancer-derived xenografts in part due to the reduced infectivity and the tumor cystic nature. The therapeutic effect of hTR promoter was found to be stronger than that of hTERT promoter. CONCLUSIONS These results demonstrate that telomerase-driven expression of NIS could potentially have applications for (131)I therapy of a wide variety of cancers. Additionally, this is the first study to report NIS-mediated (131)I therapy of melanoma tumors in vivo.

NIS Mediates Iodide Uptake in the Female Reproductive Tract and Is a Poor Prognostic Factor in Ovarian Cancer

CONTEXT The sodium iodide symporter (NIS) mediates active transport of iodide into the thyroid and the lactating mammary glands and is highly expressed in thyroid and breast carcinomas. NIS is clinically very relevant because it allows the treatment with radioiodine of thyroid cancer patients. OBJECTIVE In this study we wanted to explore whether NIS is expressed in the ovary and in ovarian cancer. METHODS/PATIENTS Methods included NIS and paired box 8 expression and function in ovarian cancer patients and rats by immunochemistry, immunoblot, RT-PCR, and iodide uptake. RESULTS Here we demonstrate for the first time that NIS is expressed in the ovary and fallopian tube and actively accumulates significant levels of radioiodide in vivo. In a large survey of menstruating women receiving radioiodide for medical purposes, 15% showed significant uptake in the normal reproductive tract. Ovarian NIS activity is influenced by the estrous cycle stage in rats, being up-regulated during peak levels of estrogens occurring immediately before the ovulation. We unveil that the regulatory mechanism underlying this phenomenon is based on the functional cooperation of estrogen receptor-α and paired box 8. We also show that NIS is highly expressed in ovarian cancer, predicting a poor prognosis in these patients. CONCLUSIONS These results provide the basis that will help minimize the impact of therapeutic doses of radioiodide on gonadal function. We also suggest that NIS is a new ovarian cancer marker, opening a door for the use of radioiodide in the diagnosis and treatment of ovarian cancer patients.

Insulin drives glucose-dependent insulinotropic peptide expression via glucose-dependent regulation of FoxO1 and LEF1/β-catenin

Minutes after ingestion of fat or carbohydrates, vesicles stored in enteroendocrine cells release their content of incretin peptide hormones that, together with absorbed glucose, enhance insulin secretion by beta-pancreatic cells. Freshly-made incretins must therefore be packed into new vesicles in anticipation of the next meal with cells adjusting new incretin production to be proportional to the level of previous insulin release and absorbed blood glucose. Here we show that insulin stimulates the expression of the major human incretin, glucose-dependent insulinotropic peptide (GIP) in enteroendocrine cells but requires glucose to do it. Akt-dependent release of FoxO1 and glucose-dependent binding of LEF1/β-catenin mediate induction of Gip expression while insulin-induced phosphorylation of β-catenin does not alter its localization or transcriptional activity in enteroendocrine cells. Our results reveal a glucose-regulated feedback loop at the entero-insular axis, where glucose levels determine basal and insulin-induced Gip expression; GIP stimulation of insulin release, physiologically ensures a fine control of glucose homeostasis. How enteroendocrine cells adjust incretin production to replace incretin stores for future use is a key issue because GIP malfunction is linked to all forms of diabetes.

Role of iodide metabolism in physiology and cancer

Iodide (I-) metabolism is crucial for the synthesis of thyroid hormones (THs) in the thyroid and the subsequent action of these hormones in the organism. I- is principally transported by the sodium iodide symporter (NIS) and by the anion exchanger PENDRIN, and recent studies have demonstrated the direct participation of new transporters including anoctamin 1 (ANO1), cystic fibrosis transmembrane conductance regulator (CFTR) and sodium multivitamin transporter (SMVT). Several of these transporters have been found expressed in various tissues, implicating them in I- recycling. New research supports the exciting idea that I- participates as a protective antioxidant and can be oxidized to hypoiodite, a potent oxidant involved in the host defense against microorganisms. This was possibly the original role of I- in biological systems, before the appearance of TH in evolution. I- per se participates in its own regulation, and new evidence indicates that it may be antineoplastic, anti-proliferative and cytotoxic in human cancer. Alterations in the expression of I- transporters are associated with tumor development in a cancer-type-dependent manner and, accordingly, NIS, CFTR and ANO1 have been proposed as tumor markers. Radioactive iodide has been the mainstay adjuvant treatment for thyroid cancer for the last seven decades by virtue of its active transport by NIS. The rapid advancement of techniques that detect radioisotopes, in particular I-, has made NIS a preferred target-specific theranostic agent.

Bases epidemiológicas y mecanismos moleculares implicados en las asociaciones de obesidad y diabetes con cáncer

The association between diabetes and cancer was hypothesized almost one century ago. Today, a vast number of epidemiological studies support that obese and diabetic populations are more likely to experience tissue-specific cancers, but the underlying molecular mechanisms remain unknown. Obesity, diabetes, and cancer share many hormonal, immune, and metabolic changes that may account for the relationship between diabetes and cancer. In addition, antidiabetic treatments may have an impact on the occurrence and course of some cancers. Moreover, some anticancer treatments may induce diabetes. These observations aroused a great controversy because of the ethical implications and the associated commercial interests. We report an epidemiological update from a mechanistic perspective that suggests the existence of many common and differential individual mechanisms linking obesity and type 1 and 2 diabetes mellitus to certain cancers. The challenge today is to identify the molecular links responsible for this association. Classification of cancers by their molecular signatures may facilitate future mechanistic and epidemiological studies.