bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1178: Loss of PHLPP expression promotes glycolysis in colon cancer cells
Authors: Xiong Xiaopeng , Wen Yang-an , Gao Tianyan 
Published: August 2015

Abstract
Increased glycolysis is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate high levels of glycolytic intermediates to support proliferation. PHLPP belongs to a novel family of Ser/Thr protein phosphatases. Our previous studies have shown that PHLPP serves as a tumor suppressor to inhibit cell proliferation, promote apoptosis and increase therapeutic sensitivity in colon cancer cells. Here, we further examined the role of PHLPP in regulating metabolic pathways in colon cancer. Our results showed that the rate of glucose consumption and lactate production was significantly increased in PHLPP knockdown colon cancer cells and in PHLPP knockout MEF cells. Metabolic analysis using Seahorse XF96 analyzer revealed that decreased PHLPP expression resulted in an increase in the extracellular acidification rate (ECAR) suggesting enhanced glycolysis. To determine the underlying molecular mechanism, we found that the Akt-mediated phosphorylation of HK2 was elevated in PHLPP knockdown colon cancer cells and the amount of mitochondria-associated hexokinase 2 (HK2) was increased. This is consistent with previous finding that Akt-mediated phosphorylation of HK2 increases its activity by promoting mitochondria translocation. Furthermore, PHLPP, Akt and HK2 were found in the same mitochondria fraction and PHLPP co-immunoprecipitated with HK2 in colon cancer cells. As HK2 is the key enzyme that determines the direction and magnitude of glucose flux, our studies identified PHLPP as a novel regulator of glucose metabolism by controlling Akt-mediated regulation of HK2 activity.
Note: This abstract was not presented at the meeting.
Citation Format: Xiaopeng Xiong, Yang-an Wen, Tianyan Gao. Loss of PHLPP expression promotes glycolysis in colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1178. doi:10.1158/1538-7445.AM2015-1178
Abstract 1185: Regulation of neutral amino acid transporters gene expression profile in non-small cell lung cancer
Authors: Massion Pierre P. , Senosain Maria , Hassanein Mohamed , Ji Xiangming , Qian Jun , hoeksema Megan 
Published: August 2015

Abstract
INTRODUCTION: In a recent study, we showed that SLC1A5, a key glutamine (Gln) transporter, regulates tumor growth and survival in NSCLC. Here we sought to characterize the expression of other Gln transporters in lung cancer and to test whether the inhibition of SLC1A5 activity induced a change in expression of other amino acid transporters in NSCLC.
METHODS: Neutral amino acid transporters reported in the cancer literature were evaluated in publically available lung cancer gene expression datasets. Among those, SLC38A1, SLC1A4, SLC1A5, SLC7A5, SLC7A11, SLC7A8 were selected for the in vitro validation. The expression of these genes was evaluated in two lung squamous carcinoma cell lines (HCC15, H226) and one adenocarcinoma cell line (A549) by RT-PCR and then quantified by qPCR, using SYBR® Green Supermix protocol. The expression of the same genes was assessed in response to transient SLC1A5 knockdown in HCC15 and A549 cell lines by qPCR.
RESULTS: Amino acid transporters SLC38A1, SLC1A5, SLC7A5 and SLC7A11 are expressed in NSCLCs, a finding that was confirmed in the three cell lines studied. SLC1A4 was found to have the lowest expression and SLC7A8 no expression in any of cell lines. In response to SLC1A5 transient knockdown in A549, SLC38A1, SLC1A4 and SLC7A5 were significantly up-regulated (p&lt;0.02); in contrast, in HCC15, SLC38A1, SLC1A4 and SLC7A5 were significantly down-regulated (p&lt;0.02) and SLC7A11 was up-regulated (p&lt;0.13).
CONCLUSION: Our results show that SLC38A1, SLC1A5, SLC7A5 and SLC7A11 have the highest level of gene expression in NSCLC. We identified a possible compensatory mechanism to satisfy Gln transport and cellular function upon SLC1A5 silencing involving different transporters in a cell-specific manner. Compensatory mechanisms in response to SLC1A5 knockdown deserve further investigation as it may have implications in strategies aiming at inhibiting its activity. Further expression, localization and functional studies will follow to better understand changes occurring in lung cancer progression.
Key words: Non-small cell lung cancer, SLC1A5, expression, amino acid, transporters
Citation Format: Pierre P. Massion, Maria Senosain, Mohamed Hassanein, Xiangming Ji, Jun Qian, Megan hoeksema. Regulation of neutral amino acid transporters gene expression profile in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1185. doi:10.1158/1538-7445.AM2015-1185
Abstract 1217: Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression
Authors: Dean Jeffry L. , Jones Jennifer K. , Goodwin Jonathan F. , Knudsen Karen E. 
Published: August 2015

Abstract
Prostatic adenocarcinoma (PCa) is the most frequently diagnosed non-cutaneous malignancy and second leading cause of cancer death in men in the US. Although organ-confined disease is manageable, treatment options for disseminated PCa are limited. First-line therapy for metastatic PCa targets the androgen receptor (AR) via androgen deprivation therapy (ADT); however, tumors often recur, displaying reactivation of AR signaling despite continued therapeutic targeting. There is currently no durable treatment for this advanced disease stage, termed castrate-resistant PCa (CRPC). While most localized PCa express wild-type p53, recent high-profile, genome-wide studies identified increased TP53 gene mutation rates in advanced disease (specifically CRPC). Using these data, we noted that the patient-derived, CRPC-specific p53 mutations observed are relatively unique to prostate cancer. These mutations occur in “hotspot” clusters altered in other tumor types, but represent distinct amino acid changes seemingly unique to prostate cancer. While the underlying consequences of these CRPC-specific p53 mutations are unknown, it was hypothesized that their presence in the DNA-binding domain of p53 protein may represent “gain-of-function” (GOF) alterations that direct the transcription factor to alternative, pro-tumorigenic gene targets. Our preliminary findings strongly support this contention and reveal that these p53 mutations are major drivers of CRPC phenotypes. Specifically, our findings demonstrate that mutant p53: 1. Selectively alter p53 activity, based on analyses of PCa-relevant p53 target genes; 2. Compromise DNA damage response; 3. Alter AR signaling and response to AR-directed therapeutics; and 4. Promote transition to castration-resistance. These data are further supported by recent longitudinal studies of patient progression, wherein the R248Q mutation was found to be a key genetic alteration identifying lethal disease. While future investigation will be directed to better understand the specific contribution of individual DDR mutations, it is clear that deregulation of DNA damage repair and response pathways is likely to underlie increased genomic instability that is observed among advanced prostate cancers.
Citation Format: Jeffry L. Dean, Jennifer K. Jones, Jonathan F. Goodwin, Karen E. Knudsen. Determining the impact of CRPC-specific p53 mutation on therapeutic response and prostate tumor progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2015-1217
Abstract 1234: Impact of cancer-associated mutations on MDM2 function
Authors: Chauhan Krishna M. , Martinez Luis A. 
Published: August 2015

Abstract
MDM2 is an E3 ubiquitin ligase that functions as a negative regulator of the tumor suppressor p53. MDM2 can promote the ubiquitination and proteasomal degradation through 26S proteasome. In addition to p53, MDM2 can ubiquitinate and promote the degradation of other proteins including SLUG, PCNA, and TERT. Although MDM2 has a well accepted role as an oncogene in human cancer, it also exhibits the ability to suppress the SLUG-driven epithelial mesenchymal transition (EMT) that is a key component of the metastasis process. The fact that MDM2 is required to suppress the SLUG-driven epithelial mesenchymal transition (EMT) led us to speculate that mutations in the MDM2 gene might impair the proteasomal degradation of key regulatory proteins that control biological events and thereby contribute to tumorogenesis. Here, we studied twenty-one somatic point mutants in MDM2 that occur in human cancer. We find that seven of these MDM2 mutants have lost the capacity to degrade p53. Of these mutants, three have lost the capacity to polyubiquitinate and two do not interact with p53. Additionally, we found that two of the mutants exhibit enhanced ability to degrade p53. We also assessed whether these mutants impacted the ability of mdm2 to degrade SLUG. Although previous studies have shown that MDM2 needs to form a trimeric complex with p53 and SLUG in order for degradation of the latter, we find that MDM2 efficiently degraded SLUG in the absence of p53. Furthermore, MDM2 mutants that do not interact with p53 still retain the ability to degrade SLUG. Our study indicates that mutations in MDM2 can yield mutant proteins that exhibit distinct capacities to degrade its substrates. Further, in vitro and in vivo studies will address the impact of these mutations on the oncogenic properties of MDM2.
Citation Format: Krishna M. Chauhan, Luis A. Martinez. Impact of cancer-associated mutations on MDM2 function. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1234. doi:10.1158/1538-7445.AM2015-1234
Abstract 1239: CDKN2B loss promotes progression from benign melanocytic nevus to melanoma
Authors: McNeal Andrew , Liu Kevin , Nakhate Vihang , Natale Christopher , Capell Brian , Dentchev Tzvete , Berger Shelley , Herlyn Meenhard , Seykora John , Ridky Todd W. 
Published: August 2015

Abstract
The CDKN2A locus on chromosome 9p21 encodes two tumor suppressors: the cyclin dependent kinase inhibitor p16INK4a and the MDM2 regulator p14ARF. Homozygous deletion of this locus is among the most common genetic events in human cancer across tissues, with the resultant selective advantage to cancer cells generally attributed to the loss of CDKN2A proteins, which help maintain functional Rb and p53. However, in greater than 90% of cancer tissues harboring CDKN2A deletion, the adjacent CDKN2B gene encoding the p15 cyclin dependent kinase inhibitor, is also deleted. The degree to which CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in common, benign melanocytic nevi (moles) expressing the constitutively active BRAF(V600E) oncogene. A large percentage of melanomas develop in continuity with these pre-existing nevi, suggesting that nevus melanocytes are not permanently senescent, and can serve as tumor-initiating cells upon acquisition of additional genetic changes. By examining primary melanocytes isolated directly from freshly excised benign human nevi, as well as normal primary melanocytes engineered to inducibly express BRAF(V600E), we link BRAF activation to a TGFβ-dependent p15 induction that arrests nevi in their pre-malignant state. We also use the primary nevus cells to establish a new genetically-defined, human in vivo melanoma xenograft model, which maximizes medical relevance by utilizing the naturally occurring melanoma precursor cells in a native 3-dimensional environment. With this approach, we show that p15 depletion in benign nevi promotes progression to melanoma, establishing the reversibility of nevus melanocyte growth arrest, and the functional importance of CDKN2B loss in human cancer.
Citation Format: Andrew McNeal, Kevin Liu, Vihang Nakhate, Christopher Natale, Brian Capell, Tzvete Dentchev, Shelley Berger, Meenhard Herlyn, John Seykora, Todd W. Ridky. CDKN2B loss promotes progression from benign melanocytic nevus to melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1239. doi:10.1158/1538-7445.AM2015-1239
Abstract 124: P21-activated protein kinase 1 high expression is a positive prognostic factor in human primary and metastatic pancreatic cancer
Authors: Yuan Shuqiang , Wang Feng , Juan Han , Pu Hengying , Zhou Zhiwei , Xu Rui-hua 
Published: August 2015

Abstract
Background: P21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies. Its overexpression was associated with poor prognosis in some tumor types including breast cancer, gastric cancer, colorectal cancer and so on. However, the expression and clinical relevance of PAK1 expression in human pancreatic cancer remain unknown.
Methods: The present study was designed to investigate the clinical and prognostic significance of PAK1 expression in pancreatic carcinoma. We examined the expression of PAK1 by immunohistochemistry in 72 primary pancreatic carcinoma samples and 20 liver metastatic samples. The relationships between PAK1 and clinicopathological parameters and prognosis in primary and metastatic pancreatic cancer were analyzed.
Results: Among the total 92 cases, primary pancreatic cancer samples had significantly higher rate (38/72, 52.8%) of high PAK1 expression than liver metastatic samples (5/20, 25.0%) (p = 0.028). In 72 primary pancreatic cancer patients, high PAK1 expression was associated with younger age (p = 0.038) and moderately or well differentiated tumor (p = 0.007). Moreover, a positive relationship was found between high PAK1 expression and overall survival (OS) (p&lt;0.005). Patients with high PAK1 expression had a better OS than those with low PAK1 expression. Univariate and multivariate analysis by Cox regression including PAK1 and other prognostic pathological markers demonstrated high PAK1 immunostaining as an independent prognostic factor for survival in pancreatic cancer patients (P&lt;0.005).
Conclusions: For the first time, we report that PAK1 is a novel prognostic marker for pathologically confirmed human pancreatic cancer. Reduced expression of p21-activated protein kinase 1 correlates with poor histological differentiation in pancreatic cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Shuqiang Yuan, Feng Wang, Han Juan, Hengying Pu, Zhiwei Zhou, Rui-hua Xu. P21-activated protein kinase 1 high expression is a positive prognostic factor in human primary and metastatic pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 124. doi:10.1158/1538-7445.AM2015-124
Abstract 127: Overexpression of neurotrophic tyrosine receptor kinases (NTRKs) as a potential therapeutic target for cancer
Authors: Wei Ge (Gina) , Cam Nicholas , Patel Roopal , Shoemaker Robert , Wild Robert , Li Gang 
Published: August 2015

Abstract
Neurotrophic tyrosine receptor kinases (NTRKs), or Tropomyosin receptor kinases (Trks), belong to a family of tyrosine kinases that regulate synaptic strength and plasticity during neural development. Deregulated kinase activity of Trk family members due to chromosomal rearrangements, gene mutations, splice variants and overexpression has been shown to be associated with cancer cell proliferation, survival, invasion and chemo-resistance in a number of cancer types. For example, chromosomal rearrangements involving NTRK1-3 have been reported in lung, colorectal, papillary thyroid, glioblastoma, melanoma and other cancers, and have been demonstrated to function as oncogenic drivers in these tumors. Moreover, overexpression of TrkA, TrkB and/or their corresponding ligands has been observed in a number of solid tumors such as breast, lung, prostate and pancreatic cancers. However, the functional implication of Trk overexpression has not been well defined or fully explored as a potential therapeutic strategy.
To characterize the expression, signaling and function of full-length Trks in cancer, a series of stable cell lines with full-length NTRK genes were established. The engineered cell lines were characterized for Trk expression, Trk phosphorylation and their response to ligand stimulation. Moreover, cell proliferation, cell transformation and growth inhibition by RXDX-101, a clinical stage, potent and selective pan-Trk inhibitor, were assessed. Trk downstream effectors, such as PLCγ, AKT and ERK, were also evaluated in the relevant settings. Furthermore, several cancer cell lines with endogenous overexpression of full-length Trks or rearranged Trks were identified and functionally characterized.
Our studies highlight the similarities and differences between Trk rearrangement and overexpression as potential oncogenic drivers and support further exploration of RXDX-101 in cancers with Trk overexpression.
Citation Format: Ge (Gina) Wei, Nicholas Cam, Roopal Patel, Robert Shoemaker, Robert Wild, Gang Li. Overexpression of neurotrophic tyrosine receptor kinases (NTRKs) as a potential therapeutic target for cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 127. doi:10.1158/1538-7445.AM2015-127
Abstract 1276: CD169-positive sinus macrophages in regional lymph nodes are associated with better survival in patients with malignant melanoma
Authors: Saito Yoichi , Ohnishi Koji , Miyashita Azusa , Nakahara Satoshi , Fujiwara Yukio , Horlad Hasita , Motoshima Takanobu , Fukushima Satoshi , Jinnin Masatoshi , Ihn Hironobu , Takeya Motohiro , Komohara Yoshihiro 
Published: August 2015

Abstract
CD169 (sialoadhesin) is a sialic acid receptor that is expressed on the particular macrophages such as lymph node sinus macrophages. Animal studies suggested that CD169+ macrophages in lymph nodes have tumor-preventing properties, but the role of these cells in human tumors has not been clarified. Therefore, we speculated that CD169+ macrophages in regional lymph nodes (RLNs) are suggested to be essential to the anti-tumor immunity and involved in the prognosis of cancer patients. To determine the significance of CD169+ macrophages in patients with malignant melanoma (MM), we examined the expression of CD169 in paraffin-embedded tissue samples from 93 patients by immunohistochemistry and their relationship with overall survival and clinicopathological factors. A high density of CD169+ cells was significantly associated with longer overall survival in patients with MM (P = 0.001). Multivariate analysis showed that the density of CD169+ cells was an independent prognostic factor. We also found that the density of CD169+ macrophage was positively correlated with the number of CD8+ cytotoxic T cells infiltrating into tumor tissues. Furthermore, interferon (IFN)-α induced strong CD169 expression on human macrophages in vitro, and IFN-α-producing cells were indeed detected surrounding CD169+ cells in lymph node. Our data support that IFN-α-producing cells may be plasmacytoid dendritic cells (pDCs) known to produce IFN-α. These results suggest that CD169+ macrophages in RLNs are intimately involved in T-cell-mediated antitumor immunity and may be a helpful marker for assessing clinical prognosis and monitoring antitumor immunity in patients with MM.
Citation Format: Yoichi Saito, Koji Ohnishi, Azusa Miyashita, Satoshi Nakahara, Yukio Fujiwara, Hasita Horlad, Takanobu Motoshima, Satoshi Fukushima, Masatoshi Jinnin, Hironobu Ihn, Motohiro Takeya, Yoshihiro Komohara. CD169-positive sinus macrophages in regional lymph nodes are associated with better survival in patients with malignant melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2015-1276
Abstract 1295: Role of glycine N-methyltransferase in the regulation of T cell responses in experimental autoimmune encephalomyelitis
Authors: Li Chung-Hsien , Lin Ming-Hong , Chen Yen-Fu , Chu Shih-Han , Tu Pang-Hsien , Fang Cheng-Chieh , Yen Chia-Hung , Liang Peir-In , Huang Jason C. , Su Yu-Chia , Sytwu Huey-Kang , Chen Yi-Ming A. 
Published: August 2015

Abstract
Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt−/− mice developed hepatocellular carcinoma, we hypothesized that Gnmt−/− mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was significantly reduced in Gnmt−/− mice. Pathological examination of the spinal cords revealed that Gnmt−/- mice had significantly lower level of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of pro-inflammatory cytokines, including IFN-gamma and IL-17A, were much lower in the spinal cord of Gnmt−/- than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T cell proliferation and induction of T helper (Th) 1 and Th17 cells were markedly suppressed in MOG35-55 induced Gnmt−/- mice. Moreover, the amount of regulatory T cells was significantly increased in these mice. When the T cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were significantly decreased in GNMT−/- CD4+ T cells via an IL-2 and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of regulatory T cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4+ T cells was much milder than in those with wild-type CD4+ T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4+ T cell functions.
Citation Format: Chung-Hsien Li, Ming-Hong Lin, Yen-Fu Chen, Shih-Han Chu, Pang-Hsien Tu, Cheng-Chieh Fang, Chia-Hung Yen, Peir-In Liang, Jason C. Huang, Yu-Chia Su, Huey-Kang Sytwu, Yi-Ming A. Chen. Role of glycine N-methyltransferase in the regulation of T cell responses in experimental autoimmune encephalomyelitis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1295. doi:10.1158/1538-7445.AM2015-1295