The molecular mechanisms responsible for the association of obesity with adverse colon cancer outcomes are poorly understood. We investigated the effects of a high-energy diet on growth of an in vivo ...colon cancer model. Seventeen days following the injection of 5×105 MC38 colon carcinoma cells, tumors from mice on the high-energy diet were approximately twice the volume of those of mice on the control diet. These findings were correlated with the observation that the high-energy diet led to elevated insulin levels, phosphorylated AKT, and increased expression of fatty acid synthase (FASN) by the tumor cells. Metformin, an antidiabetic drug, leads to the activation of AMPK and is currently under investigation for its antineoplastic activity. We observed that metformin blocked the effect of the high-energy diet on tumor growth, reduced insulin levels, and attenuated the effect of diet on phosphorylation of AKT and expression of FASN. Furthermore, the administration of metformin led to the activation of AMPK, the inhibitory phosphorylation of acetyl-CoA carboxylase, the upregulation of BNIP3 and increased apoptosis as estimated by poly (ADP-ribose) polymerase (PARP) cleavage. Prior work showed that activating mutations of PI3K are associated with increased AKT activation and adverse outcome in colon cancer; our results demonstrate that the aggressive tumor behavior associated with a high-energy diet has similar effects on this signaling pathway. Furthermore, metformin is demonstrated to reverse the effects of the high-energy diet, thus suggesting a potential role for this agent in the management of a metabolically defined subset of colon cancers.
Pharmacoepidemiologic studies provide evidence that use of metformin, a drug commonly prescribed for type II diabetes, is associated with a substantial reduction in cancer risk. Experimental models ...show that metformin inhibits the growth of certain neoplasms by cell autonomous mechanisms such as activation of AMP kinase with secondary inhibition of protein synthesis or by an indirect mechanism involving reduction in gluconeogenesis leading to a decline in insulin levels and reduced proliferation of insulin-responsive cancers. Here, we show that metformin attenuates paraquat-induced elevations in reactive oxygen species (ROS), and related DNA damage and mutations, but has no effect on similar changes induced by H(2)0(2), indicating a reduction in endogenous ROS production. Importantly, metformin also inhibited Ras-induced ROS production and DNA damage. Our results reveal previously unrecognized inhibitory effects of metformin on ROS production and somatic cell mutation, providing a novel mechanism for the reduction in cancer risk reported to be associated with exposure to this drug.
We investigated the effects of metformin on the growth of lewis lung LLC1 carcinoma in C57BL/6J mice provided with either a control diet or a high-energy diet, previously reported to lead to weight ...gain and systemic insulin resistance with hyperinsulinemia. Forty-eight male mice were randomized into four groups: control diet, control diet+metformin, high-energy diet, or high-energy diet+metformin. Following 8 weeks on the experimental diets, selected groups received metformin in their drinking water. Three weeks following the start of metformin treatment, mice were injected with 0.5×106 LLC1 cells and tumor growth was measured for 17 days. By day 17, tumors of mice on the high-energy diet were nearly twice the volume of those of mice on the control diet. This effect of diet on tumor growth was significantly attenuated by metformin, but metformin had no effect on tumor growth of the mice on the control diet. Metformin attenuated the increased insulin receptor activation associated with the high-energy diet and also led to increased phosphorylation of AMP kinase, two actions that would be expected to decrease neoplastic proliferation. These experimental results are consistent with prior hypothesis-generating epidemiological studies that suggest that metformin may reduce cancer risk and improve cancer prognosis. Finally, these results contribute to the rationale for evaluation of the anti-neoplastic activity of metformin in hyperinsulinemic cancer patients.
Numerous studies have demonstrated that functional mitochondria are required for tumorigenesis, suggesting that mitochondrial oxidative phosphorylation (OXPHOS) might be a potential target for cancer ...therapy. In this study, we investigated the effects of BAY 87-2243, a small molecule that inhibits the first OXPHOS enzyme (complex I), in melanoma in vitro and in vivo.
BAY 87-2243 decreased mitochondrial oxygen consumption and induced partial depolarization of the mitochondrial membrane potential. This was associated with increased reactive oxygen species (ROS) levels, lowering of total cellular ATP levels, activation of AMP-activated protein kinase (AMPK), and reduced cell viability. The latter was rescued by the antioxidant vitamin E and high extracellular glucose levels (25 mM), indicating the involvement of ROS-induced cell death and a dependence on glycolysis for cell survival upon BAY 87-2243 treatment. BAY 87-2243 significantly reduced tumor growth in various BRAF mutant melanoma mouse xenografts and patient-derived melanoma mouse models. Furthermore, we provide evidence that inhibition of mutated BRAF using the specific small molecule inhibitor vemurafenib increased the OXPHOS dependency of BRAF mutant melanoma cells. As a consequence, the combination of both inhibitors augmented the anti-tumor effect of BAY 87-2243 in a BRAF mutant melanoma mouse xenograft model.
Taken together, our results suggest that complex I inhibition has potential clinical applications as a single agent in melanoma and also might be efficacious in combination with BRAF inhibitors in the treatment of patients with BRAF mutant melanoma.
In mammals, proper storage and distribution of lipids in and between tissues is essential for the maintenance of energy homeostasis. Here, we show that tumour growth triggers hepatic metabolic ...dysfunction as part of the cancer cachectic phenotype, particularly by reduced hepatic very‐low‐density‐lipoprotein (VLDL) secretion and hypobetalipoproteinemia. As a molecular cachexia output pathway, hepatic levels of the transcription factor transforming growth factor beta 1‐stimulated clone (TSC) 22 D4 were increased in cancer cachexia. Mimicking high cachectic levels of TSC22D4 in healthy livers led to the inhibition of hepatic VLDL release and lipogenic genes, and diminished systemic VLDL levels under both normal and high fat dietary conditions. Liver‐specific ablation of TSC22D4 triggered hypertriglyceridemia through the induction of hepatic VLDL secretion. Furthermore, hepatic TSC22D4 expression levels were correlated with the degree of body weight loss and VLDL hypo‐secretion in cancer cachexia, and TSC22D4 deficiency rescued tumour cell‐induced metabolic dysfunction in hepatocytes. Therefore, hepatic TSC22D4 activity may represent a molecular rationale for peripheral energy deprivation in subjects with metabolic wasting diseases, including cancer cachexia.
Specific molecular programs in the liver significantly impact overall systemic energy availability and thereby further promote an energy‐deficient state in response to tumour development.
One-cell-stage embryos derived from most random-bred and inbred female mice exhibit an in vitro developmental block at the
two-cell stage in classical embryo culture media. However, embryos derived ...from many F 1 hybrids develop easily past the two-cell stage under the same conditions. This has given rise to the commonly accepted idea
that there exist blocking and nonblocking types of female mice, with only the former being prone to a two-cell block. Recently,
culture media have been improved to the point that even embryos prone to the two-cell block will develop past the block in
vitro, making it possible to study its etiology. Here, we show that either increased osmolarity or increased glucose/phosphate
levels induced the expected two-cell block in random-bred CF1 embryos and the two-cell block at increased osmolarities could
be rescued by the organic osmolyte glycine. Surprisingly, one-cell embryos from B6D2F 1 (BDF 1 ) F 1 hybrid females, considered to be nonblocking, also became blocked at the two-cell stage when osmolarity or glucose/phosphate
levels were increased. They were also similarly rescued by glycine from the osmolarity-induced block. The most evident difference
was that the purportedly nonblocking embryos became blocked at a higher threshold of osmolarity or glucose/phosphate level
than those considered prone to this developmental block. Thus, both blocking and nonblocking embryos actually exhibit a similar
two-cell block to development.
Abstract
Altered culture conditions induce a glycine-reversible 2-cell block in mouse embryos
Epidemiological studies estimate that by the year 2030, 2.16billion people worldwide will be overweight and 1.12billion will be obese 1. Besides its now established function as an endocrine organ, ...adipose tissue plays a fundamental role as an energy storage compartment. As such, adipose tissue is capable of extensive expansion or retraction depending on the energy balance or disease state of the host, a plasticity that is unparalleled in other organs and – under conditions of excessive energy intake – significantly contributes to the afore mentioned obesity pandemic. Expansion of adipose tissue is driven by both hypertrophy and hyperplasia of adipocytes, which can renew frequently to compensate for cell death. This underlines the importance of adipocyte progenitor cells within the distinct adipose tissue depots to control both energy storage and endocrine functions of adipose tissue. Here we summarize recent findings on the identity and plasticity of adipose stem cells, the involved signaling cascades, and potential clinical implications of these cells for the treatment of metabolic dysfunction in obesity. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.
► Adipocyte progenitors derive from pluripotent mesenchymal stem cells. ► Brown and white adipocytes develop from distinct cell lineages. ► Inducible brown adipocytes arise from progenitor differentiation or white adipocyte trans-differentiation. ► Recruitment of brown adipose tissue in humans may provide a novel approach to anti-obesity therapies.
Insulin regulates glucose uptake by normal tissues. Although there is evidence that certain cancers are growth-stimulated by insulin, the possibility that insulin influences tumor glucose uptake as ...assessed by
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F-2-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography (FDG-PET) has not been studied in detail. We present a model of diet-induced hyperinsulinemia associated with increased insulin receptor activation in neoplastic tissue and with increased tumor FDG-PET image intensity. Metformin abolished the diet-induced increases in serum insulin level, tumor insulin receptor activation and tumor FDG uptake associated with the high energy diet but had no effect on these measurements in mice on a control diet. These findings provide the first functional imaging correlate of the well-known adverse effect of caloric excess on cancer outcome. They demonstrate that, for a subset of neoplasms, diet and insulin are variables that affect tumor FDG uptake and have implications for design of clinical trials of metformin as an antineoplastic agent.
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