Diabetes and cancer represent two complex, diverse, chronic, and potentially fatal diseases. Cancer is the second leading cause of death, while diabetes is the seventh leading cause of death with the latter still likely underreported. There is a growing body of evidence published in recent years that suggest substantial increase in cancer incidence in diabetic patients. The worldwide prevalence of diabetes was estimated to rise from 171 million in 2000 to 366 million in 2030. About 26.9% of all people over 65 have diabetes and 60% have cancer. Overall, 8–18% of cancer patients have diabetes. In the context of epidemiology, the burden of both diseases, small association between diabetes and cancer will be clinically relevant and should translate into significant consequences for future health care solutions. This paper summarizes most of the epidemiological association studies between diabetes and cancer including studies relating to the general all-site increase of malignancies in diabetes and elevated organ-specific cancer rate in diabetes as comorbidity. Additionally, we have discussed the possible pathophysiological mechanisms that likely may be involved in promoting carcinogenesis in diabetes and the potential of different antidiabetic therapies to influence cancer incidence.

OBJECTIVE-To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells. Akt and tuberin, levels, and 8-oxoG-DNA glycosylase (OGG1) expression were measured in kidney cortical tissue of control and type 1 diabetic animals and in proximal tubular cells incubated with normal or high glucose. RESEARCH DESIGN AND METHODS-Phosphorylation ofRESULTS-In the renal cortex of diabetic rats, the increase in Akt phosphorylation is associated with enhanced phosphorylation of tuberin, decreased OGG1 protein expression, and 8-oxodG accumulation. Exposure of proximal tubular epithelial cells to high glucose causes a rapid increase in reactive oxygen species (ROS) generation that correlates with the increase in Akt and tuberin phosphorylation. High glucose also resulted in downregulation of OGG1 protein expression, paralleling its effect on Akt and tuberin. Inhibition of phosphatidylinositol 3-kinase/ Akt significantly reduced high glucose-induced tuberin phosphorylation and restored OGG1 expression. Hydrogen peroxide stimulates Akt and tuberin phosphorylation and decreases OGG1 protein expression. The antioxidant N-acetylcysteine significantly inhibited ROS generation, Akt/protein kinase B, and tuberin phosphorylation and resulted in deceased 8-oxodG accumulation and upregulation of OGG1 protein expression.CONCLUSIONS-Hyperglycemia in type 1 diabetes and treatment of proximal tubular epithelial cells with high glucose leads to phosphorylation/inactivation of tuberin and downregulation of OGG1 via a redox-dependent activation of Akt in renal tubular epithelial cells. This signaling cascade provides a mechanism of oxidative stress-mediated DNA damage in diabetes. Diabetes

p53 mediates DNA damage-induced cell-cycle arrest, apoptosis, or senescence, and it is controlled by Mdm2, which mainly ubiquitinates p53 in the nucleus and promotes p53 nuclear export and degradation. By searching for the kinases responsible for Mdm2 S163 phosphorylation under genotoxic stress, we identified S6K1 as a multifaceted regulator of Mdm2. DNA damage activates mTOR-S6K1 through p38a MAPK. The activated S6K1 forms a tighter complex with Mdm2, inhibits Mdm2-mediated p53 ubiquitination, and promotes p53 induction, in addition to phosphorylating Mdm2 on S163. Deactivation of mTOR-S6K1 signalling leads to Mdm2 nuclear translocation, which is facilitated by S163 phosphorylation, a reduction in p53 induction, and an alteration in p53-dependent cell death. These findings thus establish mTOR-S6K1 as a novel regulator of p53 in DNA damage response and likely in tumorigenesis. S6K1-Mdm2 interaction presents a route for cells to incorporate the metabolic/energy cues into DNA damage response and links the aging-controlling Mdm2-p53 and mTOR-S6K pathways.

Aims To identify distinct temporal likelihoods of age-related comorbidity (ARC) diagnoses: cardiovascular diseases (CVD), cancer, depression, dementia, and frailty-related diseases (FRD) in older men with type 2 diabetes (T2D) but ARC naïve initially, and assess the heterogeneous effects of metformin on ARCs and mortality. Methods We identified a clinical cohort of male veterans in the United States who were ≥ 65 years old with T2D and free from ARCs during 2002–2003. ARC diagnoses during 2004–2012 were analyzed using latent class modeling adjusted for confounders. Results The cohort consisted of 41,204 T2D men with age 74.6 ± 5.8 years, HbA1c 6.5 ± 0.97%, and 8393 (20.4%) metformin users. Four ARC classes were identified. ‘Healthy Class’ (53.6%): metformin reduced likelihoods of all ARCs (from 0.14% in dementia to 6.1% in CVD). ‘High Cancer Risk Class’ (11.6%): metformin reduced likelihoods of CVD (13.3%), cancer (45.5%), depression (5.0%), and FRD (13.7%). ‘High CVD Risk Class’ (17.4%): metformin reduced likelihoods of CVD (48.6%), cancer (3.2%), depression (2.8%), and FRD (6.3%). ‘High Frailty Risk Class’ (17.2%): metformin reduced likelihoods of CVD (18.8%), cancer (3.9%), dementia (3.8%), depression (15.6%), and FRD (23.8%). Conclusions Metformin slowed ARC development in old men with T2D, and these effects varied by ARC phenotype.

Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid related factor 2 (NRF2), and increased 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4- fluoroglutamine (18F-FGln) compared to the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage ccRCC patients who are likely to respond to glutaminase inhibitors in the clinic.

Nutrients are absorbed solely by the intestinal villi. Aging of this organ causes malabsorption and associated illnesses, yet its aging mechanisms remain unclear. Here, we show that aging-caused intestinal villus structural and functional decline is regulated by mTORC1, a sensor of nutrients and growth factors, which is highly activated in intestinal stem and progenitor cells in geriatric mice. These aging phenotypes are recapitulated in intestinal stem cell-specific Tsc1 knockout mice. Mechanistically, mTORC1 activation increases protein synthesis of MKK6 and augments activation of the p38 MAPK-p53 pathway, leading to decreases in the number and activity of intestinal stem cells as well as villus size and density. Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.

Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose (HG) induces apoptosis is not fully understood. Because the tuberin/mTOR pathway can modulate apoptosis, we studied the role of this pathway in apoptosis in type I diabetes and in cultured proximal tubular epithelial (PTE) cells exposed to HG. Compared with control rats, diabetic rats had more apoptotic cells in the kidney cortex. Induction of diabetes also increased phosphorylation of tuberin in association with mTOR activation (measured by p70S6K phosphorylation), inactivation of Bcl-2, increased cytosolic cytochrome c expression, activation of caspase 3, and cleavage of PARP; insulin treatment prevented these changes. In vitro, exposure of PTE cells to HG increased phosphorylation of tuberin and p70S6K, phosphorylation of Bcl-2, expression of cytosolic cytochrome c, and caspase 3 activity. High glucose induced translocation of the caspase substrate YY1 from the cytoplasm to the nucleus and enhanced cleavage of PARP. Pretreatment the cells with the mTOR inhibitor rapamycin reduced the number of apoptotic cells induced by HG and the downstream effects of mTOR activation noted above. Furthermore, gene silencing of tuberin with siRNA decreased cleavage of PARP. These data show that the tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes, mediated in part by cleavage of PARP by YY1.

Mutations in the tuberous sclerosis tumor suppressor genes (TSC1 and TSC2) result in autosomal dominant diseases characterized by benign tumors (hamartomas) in the kidney, heart, brain, and other organs (1). Approximately 1 in 6000 live births is linked to a germ line-inactivating mutation of either of the two genes, TSC1 or TSC2. Thus, each mutated gene accounts for ϳ50% of the cases (2). TSC2 associates with TSC1 to form the active signaling complex (3). The C terminus of TSC2 contains a GTPase-activating protein domain, which blocks mTOR activity by increasing hydrolysis of GTP associated with the small G-protein Rheb (Ras homolog enriched in the brain) (4, 5). Growth factor-stimulated Akt and other kinases phosphorylate TSC2 at specific sites, resulting in its dissociation from the TSC1/2 complex (6 -9).The lipid phosphatase activity of the tumor suppressor PTEN dephosphorylates the second messenger phosphatidylinositol (PI) 5 3,4,5-trisphosphate, thus negatively regulating the PI 3-kinase signaling pathway (10). Germ line mutations in PTEN cause cancer predisposition syndromes, such as Cowden disease (11-13). Also, loss of PTEN is common in many tumors, including sporadic glioblastoma, endometrial carcinoma, melanoma, meningioma, and renal, breast, prostate, and small cell lung cancer (11-13). Whereas PTEN deficiency predisposes to malignancy, it is rare in TSC patients (11,13,14). In PTENdeficient cancer cells, even in the absence of growth factors, Akt is constitutively active, which results in phosphorylation and inactivation of TSC2 and activation of mTOR (8, 10, 15). Similarly, the disruption of TSC2 results in significantly increased mTOR activity (16 -18). In the latter case, the mTOR activation leads to inactivation of Akt through a negative feedback loop involving IRS (insulin receptor substrate) proteins (17, 19 -21). However, additional signaling pathway(s) probably contribute to reduced Akt activation in TSC2 deficiency.In this report, we demonstrate that TSC2 deficiency results in increased expression of PTEN. As a mechanism, we show that HIF1␣ positively regulates the transcription of PTEN, using a canonical HIF-responsive element. Furthermore, we demonstrate that renal angiomyolipomas in TSC patients express elevated levels of HIF1␣ and PTEN protein. Thus, increased levels of PTEN in renal angiomyolipomas of patients with TSC may mute the malignant potential of these tumors by decreasing Akt activation. MATERIALS AND METHODS Cell Culture and Adenovirus Infection-Tsc2ϩ/ϩ and Tsc2 Ϫ/Ϫ MEFs, generously provided by Dr. D. J. Kwiatkowski (Harvard University), were grown in DMEM with low glucose with 10% fetal bovine serum (22,23). 293 cells were grown in DMEM with high glucose-containing 10% serum. All cell stocks were maintained in the presence of plasmocin and primocin. Tsc2 Ϫ/Ϫ MEFs were infected with adenovirus vector expressing TSC2. This viral vector also expressed green fluorescence protein to detect efficient infection. As a control, an adenovirus vector expressing ␤-galactosidase was used.