bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4823: Body mass index (BMI), change in BMI, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)
Authors: Sue Laura Y. , Genkinger Jeanine M. , Schairer Catherine , Ziegler Regina G. 
Published: February 2011

Abstract
Mid-life body mass index (BMI) has been consistently and positively associated with risk of postmenopausal breast cancer, but BMI at younger ages has been inversely associated with risk. Few studies have looked at the timing of adult BMI change and risk. Our analysis of adult BMI, BMI change, and postmenopausal breast cancer risk is, to our knowledge, the largest study to date. Our study population included 72,007 women, 55-74 years old at baseline, in the PLCO cohort: 3,677 postmenopausal breast cancer cases were ascertained from 1993 to 2007 (median follow-up, 9.9 y; interdecile range, 6.2 -12.9 y). Cox proportional hazards models were used to estimate multivariate relative risks (RRs) and 95% confidence intervals (95% CIs). BMI at age 20 and postmenopausal breast cancer risk were consistently inversely associated across use of menopausal hormone therapy (MHT) (Ptrend = 0.01). As the positive association between BMI at study baseline and breast cancer risk appeared to be limited to women who had never used MHT, we present these results among women who never used MHT. Postmenopausal breast cancer risk increased steadily across categories of increasing BMI at study baseline (Ptrend &lt;0.0001) regardless of BMI at age 20. Furthermore, being overweight or obese (&gt;25 kg/m2) at both study baseline and at age 20 had a protective effect on postmenopausal breast cancer risk, compared to being overweight or obese at study baseline but having a normal BMI (&lt;25 kg/m2) at age 20. The RR of postmenopausal breast cancer for a BMI gain &gt;5 kg/m2 between age 20 and age 50 was 1.82 (95% CI, 1.45-2.30), compared to women with no change in BMI (+/− 1 kg/m2). The RR for the same BMI gain from age 50 to age at baseline was 1.56 (95% CI, 1.29-1.90), compared to women with no change in BMI. In addition, in women who gained &gt;5 kg/m2 between age 20 and age at baseline, postmenopausal breast cancer risk nearly doubled (RR, 1.93; 95% CI, 1.46-2.62), compared to the combined group of women with no change in BMI or with BMI loss (&lt;-1 kg/m2). Among women who had never used MHT, BMI gain before and after age 50 was associated with increased postmenopausal breast cancer risk. Our study suggests that, with respect to postmenopausal breast cancer, healthy weight maintenance throughout adulthood is important and that BMI gain from age 20 to age 50 may play a particularly important role in increasing risk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4823.
Abstract 4830: Insulin-like growth factors and kidney cancer risk in men
Authors: Major Jacqueline M. , Pollak Michael N. , Snyder Kirk , Virtamo Jarmo , Albanes Demetrius 
Published: February 2011

Abstract
Context: Causes of kidney cancer are not fully understood. Incidence is highest in those ages 50 to 70, and almost twice as high in men as in women. Smokers are twice as likely as non-smokers to develop renal cell carcinoma and about four times as likely to develop cancer of the renal pelvis. Insulin-like growth factor-I (IGF-I) has been shown to increase kidney microvascular growth and glomerular filtration rate, and its administration increases renal function in animal models of chronic renal failure, and has been proposed as a possible therapeutic agent (Hirschberg et al, 1998). However, the possible roles of IGF in the development of kidney cancer have not been well-studied. Objective: To examine the relation of serum levels of IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) to kidney cancer risk. Methods: We conducted a case-cohort study nested within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of 29,133 Finnish male smokers who were 50-69 years of age and not diagnosed with cancer at study entry. Serum concentrations of IGF-I, IGFBP-3 were measured in blood samples collected in 1985 to 1988. One hundred men were identified who had a diagnosis of kidney cancer &gt;5 years after blood collection through the end of 1997. Self-reported information on lifestyle and medical history was collected and weight and height were measured at baseline. Multivariable logistic regression models were used to estimate the relative risk of kidney cancer associated with IGF levels. Results: A history of hypertension (known to be increased in those who are older, overweight, or heavier smokers) was more common among cases than among noncases. Men with IGF-I levels &gt;108 ng/mL were 63% less likely to develop kidney cancer than men with IGF-I levels ≤108 ng/mL (OR=0.37; 95% CI=0.20-0.69). IGFBP-3 levels did not alter the association between IGF-I and kidney cancer risk. Further, no association was observed between IGFBP-3 levels and the development of kidney cancer. Conclusions: Low serum IGF-I levels in this cohort of older middle-aged male smokers are associated with increased kidney cancer risk, independent of IGFBP-3, age, anthropometry, lifestyle and medical history. Further research is needed to confirm the findings and examine the association in women and non-smokers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4830.
Abstract 4834: Energy-dependent AMPK association with the ULK1-mTORC1 complex regulates autophagy
Authors: Lee Jong Woo , Park Sungman , Yoshinori Takahashi , Wang Hong Gang 
Published: February 2011

Abstract
Autophagy is an intracellular catabolic process through which bulky cytosolic components are sequestered for lysosomal degradation. Recent evidence suggests that mTOR suppresses autophagy through direct interaction with the ULK1-Atg13-FIP200 complex. However, the mechanism by which mTOR is controlled to activate ULK1 activity for autophagy induction is not yet well elucidated. Using tandem affinity purification (TAP) assay, we screened for ULK1 binding proteins and identified several additional ULK1 binding proteins that mediate the pro-autophagic activity of ULK1. Here we report AMP-activated protein kinase (AMPK), which is known to be a highly-conserved cellular energy sensor that is activated under conditions of low intracellular ATP, as a new ULK1 binding protein. We found that AMPK binds to the PS domain of ULK1 in an energy-dependent manner, whereas mTOR associates with ULK1 through raptor interaction with the kinase domain of ULK1 independently of nutrient availability. Mechanistically, AMPK inhibits the mTOR activity by recruiting 14-3-3 to the mTORC1 through phosphorylation of raptor in response to energy stress. Importantly, activation of AMPK by 5-amino-4-imidazolecarboxamide ribose (AICAR) is able to suppress the mTORC1 and induce autophagy in TSC2-deficient cells with wild-type raptor but not the mutant raptor (S722A/S792A) lacking AMPK phosphorylation sites. Our study indicates, therefore, that AMPK-mediated raptor phosphorylation plays an important role in the activation of ULK1 to induce autophagy under energy stress conditions.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4834.
Abstract 4835: Bif-1 induces the fission of Golgi membranes to generate Atg9-containing vesicles for autophagosome formation
Authors: Takahashi Yoshinori , Meyerkord Cheryl L. , Gonsar Kristin , Hori Tsukasa , Wang Hong-Gang 
Published: February 2011

Abstract
Dysregulation of autophagy, an intracellular bulk degradation system, is strongly associated with the pathogenesis of a number of diseases, including cancer. Despite the identification of 31 genes that are essential for autophagy, the molecular machineries that regulate the generation and expansion of autophagosomal membranes are not fully understood. We have previously reported that Bif-1 interacts with Beclin 1 through UVRAG and that loss of Bif-1 suppresses the formation of autophagosomes during starvation. Here, we provide further evidence that Bif-1 acts with the PI3KC3 complex II (Beclin 1-UVRAG-PI3KC3; PI3KC3C2) to regulate the formation of autophagosomes by regulating the trafficking of the membrane-integrated, autophagy-related (Atg) protein, Atg9, by inducing the fission of Golgi membranes during the induction of autophagy. In response to starvation, Bif-1 co-accumulates with Atg9 in cytosolic foci that are positive for Golgi complex-derived membranes. Loss of Bif-1 or inhibition of the PI3KC3C2 not only suppresses the fragmentation of Golgi membranes and the Atg9-containing vesicles that are induced by nutrient starvation or rapamycin treatment, but also results in the accumulation of Atg9 at the Golgi complex. Importantly, Bif-1 mutants, which lack membrane binding and/or bending activity by deletion of the helix 0, helix 1 insertion, or both regions of the Bif-1 N-BAR domain, fail to restore rapamycin-induced formation of Atg9 foci and autophagosomes in Bif-1-deficient cells. Furthermore, immunoelectron microscopic analyses reveal that Atg9 localizes not only to autophagosomal membranes but also crescent-shaped isolation membrane-like structures during starvation. These results suggest that Bif-1, together with the PI3KC3C2, plays a key role in the fission of Golgi membranes, which generates Atg9-containing vesicles for the formation and expansion of autophagosomal membranes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4835.
Abstract 4836: RB/E2F1 in the crossroad of autophagy and apoptosis
Authors: Jiang Hong , Martin Vanesa , Gomez-Manzano Candelaria , Johnson David G. , Alonso Marta , White Erin J. , Xu Jing , McDonnell Timothy J. , Shinojima Naoki , Fueyo Juan 
Published: February 2011

Abstract
Autophagy is a protective mechanism that renders cells viable in stressful conditions. Mounting evidence suggests that this cellular process is also a tumor suppressor pathway. We hypothesized that retinoblastoma protein (RB), a key tumor suppressor, induces autophagy. To test this hypothesis, we first transduced RB into RB-defective human cancer cells: sarcoma osteogenic (Saos-2) cells, hepatoma (Hep3B) cells, and brain tumor stem cells (MDNSC23). The ectopic RB induced autophagy as demonstrated by significantly increased percentage of cells with acidic vesicular organelles (from less than 10% to more than 30%, P &lt; 0.05), and the lipidation of LC3-I leading to the formation of autophagosomes/autolysosomes that were visualized by EGFP-LC3 punctation (from less than 20% to more than 80%, P = 0.003). These double-membraned vesicles were clearly shown by ultrastructural study via transmission electron microscopy. However, when Beclin 1 was silenced with siRNA in Saos-2 cells, the RB-mediated autophagy was blocked. In addition, study of autophagy flux with Saos-2 cells expressing double-tagged mRFP-EGFP-LC3 fusion protein revealed that RB stimulated the formation and maturation of autophagosomes. Consistently, RB activators p16INK4a and p27/kip1 caused autophagy in an RB-dependent manner. Importantly, we found RB mutants Delta-22 and R661W deficient for binding E2F failed to induce autophagy. Moreover, E2F1 overexpression antagonized RB-mediated autophagy, leading to apoptosis in Saos-2 cells. In agreement with the above observations, silencing E2F1 with siRNA resulted in autophagy in U-87 MG cells; and autophagy levels increased from 4% in wild-type MEFs to 40% in E2F1 knockout MEFs (P = 0.002). Collectively, our data reveal that RB/E2F1 plays a key role in the decision of a cell to undergo autophagy or apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4836.
Abstract 4838: Alpha-methyltryptophan, a blocker of the amino acid transporter SLC6A14, induces autophagy and apoptosis in SLC6A14-positive breast cancer and colon cancer cell lines
Authors: Karunakaran Senthil , Schoenlein Patricia V. , Thangaraju Muthusamy , Prasad Puttur D. , Ganapathy Vadivel 
Published: February 2011

Abstract
SLC6A14 (also known as ATB0,+) is a Na+/Cl− -coupled amino acid transporter that transports 18 of the 20 proteinogenic amino acids, including all essential amino acids. Normal tissues express this transporter at low levels, whereas tumor tissues (colon, breast, and cervix) upregulate this transporter several-fold. The unique functional features of SLC6A14 (broad substrate specificity and multiple driving forces) make it an ideal transporter for tumor cells to maintain amino acid nutrition necessary for enhanced cell proliferation. We speculate that SLC6A14 could not only be an ideal tumor-specific delivery system for amino acid-based anti-cancer drugs but also be a direct drug target for cancer chemotherapy. Recently we identified alpha-methyltryptophan (ALT) as a blocker of SLC6A14. Here we examine the potential of this blocker as an anti-cancer agent in SLC6A14-positive breast and colon cancer cells. Treatment of MCF7 (a breast cancer cell line), HCT116 and LS174T (colon cancer cell lines) with ALT causes amino acid starvation as evidenced by the upregulation of asparagine synthetase and CHOP. These three cell lines are SLC6A14-positive. In contrast, ALT treatment of breast cancer cell line MDA-MB231, which is SLC6A14-negative, does not show any evidence of amino acid starvation. Similarly, ALT treatment has no effect on normal breast and colon epithelial cell lines (MCF10A and CCD841, respectively). These cell lines also do not express SLC6A14. These data show that ALT-induced amino acid starvation is mediated specifically through the blockade of SLC6A14. Since nutrient signaling is also associated with changes in mTOR pathway, we examined the influence of ALT treatment on phosphorylation of S6 and S6kinase. Blockade of SLC6A14 with ALT in SLC6A14-positive cancer cell lines leads to decreased mTOR signaling as evidenced by decreased phosphorylation of S6 and S6kinase. Again, such changes are not seen in SLC6A14-negative cancer or normal cell lines. The initial response of the SLC6A14-positive cancer cell lines to ALT treatment is induction of autophagy. ALT-induced autophagy is documented in these cells by light and electron microscopic examination as well as by biochemical means. Inhibition of autophagy with 3-methyladenine under these conditions leads to apoptosis. We conclude that SLC6A14 is a potential drug target for cancer chemotherapy and that ALT could serve as a lead compound for the future design of high-affinity blockers of SLC6A14.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4838.
Abstract 4840: 2-Deoxy-D-glucose induces autophagy through endoplasmic reticulum stress rather than by lowering ATP
Authors: Xi Haibin , Kurtoglu Metin , Liu Huaping , Wangpaichitr Medhi , You Min , Savaraj Niramol , Lampidis Theodore J. 
Published: February 2011

Abstract
Based on emerging evidence that oncogenes direct increased glucose metabolism in tumor cells, the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) appears to be a promising drug to selectively target cancer cells. 2-DG however, not only blocks glycolysis and reduces cellular ATP production but also interferes with N-linked glycosylation, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Both bioenergetic challenge and ER stress/UPR have been shown to activate autophagy, a bulk cellular degradation process that plays either a pro- or anti-death role. This led us to investigate the following, 1) which pathway that 2-DG interferes with is responsible for stimulating autophagy, and 2) the role of autophagy in modulating 2-DG-induced cellular responses and toxicity. In four cancer cell lines (1420, MDA-MB-435, SKBR3 and T98G) we find that 2-DG upregulates autophagy (LC3B II), increases the ER stress/UPR markers, Grp78 and CHOP, and lowers ATP levels. Addition of exogenous mannose reverses 2-DG-induced autophagy and expression of GRP78 and CHOP but does not recover the lowered levels of ATP. Additionally, when autophagy is either blocked or enhanced by 3-methyladenine (3-MA) or rapamycin, respectively, 3-MA increases whereas rapamycin reduces cancer cell sensitivity to 2-DG. In support of these results, knock down of autophagy-related gene 7 (Atg7) with small interfering RNAs (siRNAs) increases sensitivity to 2-DG in 1420 cells, which correlates with increases in the ER stress/UPR markers as well as the apoptotic marker, cleaved caspase 3. Overall, these results indicate that the major mechanism by which 2-DG stimulates autophagy is through ER stress/UPR, and autophagy protects cells from 2-DG-induced toxicity through relief of ER stress. Thus, combining autophagy inhibitors with 2-DG may be useful clinically.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4840.
Abstract 4842: Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) is associated with spontaneous regression of neuroblastomas
Authors: Inoue Jun , Misawa Akiko , Tanaka Yukichi , Ichinose Shizuko , Sugino Yuriko , Hosoi Hajime , Sugimoto Tohru , Imoto Issei , Inazawa Johji 
Published: February 2011

Abstract
Background; Neuroblastoma (NB) is the most frequently occurring solid tumor in children, and shows heterogeneous clinical behavior. Favorable tumors, which are usually detected by mass screening based on increased levels of catecholamines in urine, regress spontaneously via programmed cell death (PCD) or mature through differentiation into benign ganglioneuroma (GN). In contrast, advanced-type NB tumors often grow aggressively, despite intensive chemotherapy. Understanding the molecular mechanisms of PCD during spontaneous regression in favorable NB tumors, as well as identifying genes with a pro-death role, is a matter of urgency for developing novel approaches to the treatment of advanced-type NB tumors.
Key findings; We found that the expression of lysosomal associated protein multispanning transmembrane 5 (LAPTM5) was usually down-regulated due to DNA methylation in an NB cell-specific manner, but up-regulated in degenerating NB cells within locally regressing areas of favorable tumors detected by mass-screening. Experiments in vitro showed that not only a restoration of its expression but also the accumulation of LAPTM5 protein, was required to induce non-apoptotic cell death with autophagic vacuoles and lysosomal destabilization with lysosomal-membrane permeabilization (LMP) in a caspase-independent manner. While autophagy is a membrane-trafficking pathway to degrade the proteins in lysosomes, the LAPTM5-mediated lysosomal destabilization with LMP leads to an interruption of autophagic flux, resulting in the accumulation of immature autophagic vacuoles, p62/SQSTM1, and ubiqitinated proteins as substrates of autophagic degradation. In addition, ubiquitin-positive inclusion bodies appeared in degenerating NB cells.
Conclusions; We propose a novel molecular mechanism for PCD with the accumulation of autophagic vacuoles due to LAPTM5-mediated lysosomal destabilization. LAPTM5-induced cell death is lysosomal cell death with impaired autophagy, not cell death by autophagy, so-called autophagic cell death. Thus LAPTM5-mediated PCD is closely associated with the spontaneous regression of NBs and opens new avenues for exploring innovative clinical interventions for this tumor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4842.
Abstract 4851: BH-3 mimetics radiosensitizes human prostate cancer via modulating autophagy
Authors: Lian Jiqin , Wu Xiaoqing , Tang Wenhua , Karnak David , He Fengtian , Meng Yang , Lawrence Theodore S. , Xu Liang 
Published: February 2011

Abstract
Radioresistance markedly impair the efficacy of cancer therapy and involve anti-apoptotic signal transduction pathways that prevent the treatment-induced cell death. Anti-apoptotic Bcl-2 family proteins such as Bcl-xL, Bcl-2 and Mcl-1 are overexpressed in prostate cancer and contribute to prostate tumor initiation, progression and resistance to radiotherapy. (−)-Gossypol, a natural product from cottonseed, has recently been identified as a potent small molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 and is now in advanced clinical trials. Since Bcl-2 also inhibits autophagy and radiation induces autophagy, we hypothesize that (−)-gossypol may improve prostate cancer's response to radiotherapy by inducing autophagy in apoptosis-resistant prostate cancer cells with high Bcl-2.
(−)-Gossypol inhibits tumor cell growth and preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and resistant to apoptosis, both in vitro and in vivo, but not in cells with low Bcl-2. (−)-Gossypol radiosensitized AI-prostate cancer PC-3 and CL-1 cells in clonogenic assay. (−)-Gossypol increased autophagy induced by X-ray radiation in these cells. Orally administered (−)-gossypol achieved a much greater efficacy with long-term tumor regression when used in combination with ionizing radiation. Immunoprecipitation /pull-down assay showed that (−)-gossypol induced autophagy via blocking Bcl-2-Beclin1 interaction, together with downregulating Bcl-2, upregulating Beclin1 and activating autophagic pathway signaling. Knockdown of the Beclin1 or atg5 expression blocked the autophagy induced by (−)-gossypol or radiation.
Taken together, our data demonstrate that (−)-Gossypol exerts its radiosensitizing activity through promoting radiation-induced autophagy, via modulating Bcl-2-Beclin1 interaction and atg5. (−)-Gossypol significantly enhances the anti-tumor activity of radiotherapy in vitro and in vivo, and represents a promising new regime for treatment of hormone-refractory human prostate cancer with overexpression of Bcl-2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4851.