bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3656: Cooperation of Rab25 loss with oncogenes in breast cancer
Authors: Rao Krishna A. , Joshi Pooja S. 
Published: July 2016

Abstract
Breast cancer is the most common type of cancer in females worldwide. A number of genes such as BRCA1, BRCA-2, Hras, and p53 undergo mutations and contribute to tumorigenesis of the mammary tissue. The RAB guanosine triphosphates (RAS-related in brain) belong to the Ras superfamily of GTPases. The human RAS family consists of 3 proto oncogenes - H-ras, K-ras, N-ras. Rab 25 belongs to the Rab11 subfamily and plays an important role in vesicular trafficking. The Rab proteins are ubiquitously expressed. Loss of Rab 25 expression has been reported in a number of breast cancer cases and in transformed mammary cell lines containing H-ras point mutations.
Human Mammary Epithelial Cells (HMEC) were obtained from healthy individuals undergoing reduction mammoplasty. The cells were immortalized by transducing with LXSN CDK4 R24C. This was followed by transduction with hTERT, catalytic subunit of the telomerase enzyme.
In this study, we are trying to understand if loss of Rab25 expression in HMEC co-operates with wild and mutant H-ras as well as other oncogenes and contributes to tumorigenesis. HMEC lines in which Rab25 has been knocked down were transduced with various oncogenes, including wild type and mutant H-ras, Her-2, and IGFR1. We examined the co-operativity between loss of Rab25 and these oncogenes in migration, anchorage independent growth, stem cell marker expression, and also in vivo tumorigenesis and metastasis in nude mice.
Citation Format: Krishna A. Rao, Pooja S. Joshi. Cooperation of Rab25 loss with oncogenes in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3656.
Abstract 3662: Analysis of the tumor suppressor function of B55alpha, the PP2A regulatory subunit encoded by PPP2R2A, in prostate cancer cells
Authors: Zhao Ziran , kurimchak Alison , Adeyemi Mary , Woodruff Patrick , Kolenko Vladimir , Graña Xavier 
Published: July 2016

Abstract
Genome wide DNA copy number studies in prostate cancer (PCa) have identified deletions on chromosome 8p21.2 affecting the PPP2R2A gene, which encodes B55α, a B regulatory subunit of Protein Phosphatase 2A (PP2A). The frequency of PPP2R2A hemizygous and homozygous deletions in prostate tumors is 38-58% and 2-7%, respectively. Moreover, PPP2R2A hemizygous loss correlates with reduced mRNA expression. In contrast, no significant correlation is observed for NKX3.1, a tumor suppressor also located at 8p21.2. Bioinformatics analysis indicates that PPP2R2A may belong to the class of “mutator alterations” occurring early in tumorigenesis that promote driver gene mutations. Indeed, PCa patients with these alterations exhibit reduced disease free progression. PP2A consists of a collection of trimeric holoenzymes whose substrate specificity and function is determined by the regulatory B subunit. There are 14 B subunit genes. While it is well accepted that PP2A plays a key tumor suppressor function in human cells, the particular holoenzyme(s) implicated in different tumor types is unclear. We have found, that limited ectopic expression of B55α in PCa cell lines that naturally express low levels of B55α results in dramatic toxicity. We have linked this to G2/M arrest, without concomitant loss in DNA replication, which leads to euploidy, nuclear enlargement and cell death. Thus, early hemizygous loss of PPP2R2A may facilitate effective mitotic progression. We have also seen that increased expression of B55α in these cells dramatically reduces their tumorigenic potential in SCID mice. Moreover, we observe inhibition in the phosphorylation of PP2A/B55α substrates when B55α activity is reconstituted, including AKT and pRB, suggesting alterations in multiple cancer pathways when B55α is downregulated in tumor cells. Interestingly, treatment of PC3 cells with PP2A activating drugs mimic cell cycle effects seen with B55α reconstitution.
Citation Format: Ziran Zhao, Alison kurimchak, Mary Adeyemi, Patrick Woodruff, Vladimir Kolenko, Xavier Graña. Analysis of the tumor suppressor function of B55alpha, the PP2A regulatory subunit encoded by PPP2R2A, in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3662.
Abstract 3668: Investigating a tumor suppressor role for Parkinson's susceptibility gene LRRK2 in lung cancer
Authors: Lebovitz Chandra , Chow Norman , Lam Wan , Gorski Sharon 
Published: July 2016

Abstract
In this study we investigate a novel and previously untested research question: does a known disease susceptibility gene in Parkinson's disease (PD) also act as a tumor suppressor gene in lung cancer? Our screen of publicly available cancer patient sequence data for genome and transcriptome alterations of genes that modulate autophagy, an important tumor cell survival process, revealed a dramatic loss of gene expression of Leucine-rich repeat kinase 2 (LRRK2) in non-small cell lung tumors compared to matched normal tissue. We further confirmed reduced or absent LRRK2 protein expression in a panel of lung cancer cell lines. Activating kinase-domain mutations in LRRK2 and their effect on autophagy in neuronal cell types is under study in PD; however, the pathological role of altered LRRK2 in cancer and its effect on autophagy status and tumorigenicity is completely unexplored. Pharmacological inhibition of the LRRK2 kinase domain was recently shown to stimulate autophagy in PD cell lines, while many tumors are thought to exploit elevated autophagy to survive metabolic stress and chemotherapy. Ongoing clinical trials are testing combination autophagy inhibition with current standard of care treatments in multiple cancers. Therefore, a better understanding of pathogenic LRRK2-mediated autophagy in lung cancer could form the basis of a new approach to help identify lung cancer patients that may benefit from treatment strategies employing autophagy inhibitors. Our preliminary data indicates that LRRK2 knockdown in lung cancer cell lines leads to altered cellular phenotypes and increased protein levels of a known lung cancer gene. We are further testing whether genetic and/or pharmacological inhibition of LRRK2 facilitates tumorigenesis in standard murine models of lung cancer. Our investigation of the biological relevance and therapeutic potential of a surprising discovery linking neurodegenerative disease-associated LRRK2 and lung cancer may uncover a new tumor suppressor gene and provide a novel marker (i.e. LRRK2 loss) to aid in lung cancer detection.
Citation Format: Chandra Lebovitz, Norman Chow, Wan Lam, Sharon Gorski. Investigating a tumor suppressor role for Parkinson's susceptibility gene LRRK2 in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3668.
Abstract 3675: Loss of Pkhd1 promotes intestinal tumorigenesis in Apc mice
Authors: Hu Bo , Li Wei , Qiu Qingchao , He Zhengxi , He Xiusheng , Wu Guanqing 
Published: July 2016

Abstract
Objectives: PKHD1 (Polycystic Kidney and Hepatic Disease 1), a causal gene for ARPKD (Autosomal Recessive Polycystic Kidney Disease), has been proposed to play a role in the colorectal carcinogenesis. This study is to explore the role of PKHD1 in colorectal carcinogenesis.
Methods: Mouse model with Pkhd1 mutation (Pkhd1-/-) was used to mate with ApcMin/+ mouse in the same genetic background. The resulting ApcMin/+ mice with and without Pkhd1-/- alleles were randomly sorted into two experimental groups (i.e. Pkhd1-/-;ApcMin/+ n = 36; ApcMin/+ n = 23). Tumorigenic susceptibility of Pkhd1-/-;ApcMin/+ and ApcMin/+ mice was compared. The number, size, pathology of intestinal tumors in the mice were analyzed at the age of 1-, 3-, and 6-month. The survival rates were investigated in the two groups of mice.
Results: There was no statistical difference in tumor number and size between 1-month-old ApcMin/+ and Pkhd1-/-;ApcMin/+ mice. However, the number and size of the intestinal tumors in 3- and 6-month-old Pkhd1-/-;ApcMin/+ mice were significantly increased compared with those of ApcMin/+ mice alone (P = 0.017,P = 0.022). In addition, the pathology of tumors was also analyzed between the two groups. There was no pathological difference between 1-month-old ApcMin/+ and Pkhd1-/-;ApcMin/+ mice. However, at 3-month-old, Pkhd1-/-;ApcMin/+ mice exhibited severer atypical hyperplasia in the intestinal tumor than those of ApcMin/+ mice; while at 6-month-old, focal necrosis were often seen in intestinal tumors of Pkhd1-/-;ApcMin/+ mice, but none from ApcMin/+ mice. Strikingly, tumor infiltration into the muscular mucosa was also seen in a 6-month-old Pkhd1-/-;ApcMin/+ mice. There was no statistically survival difference between ApcMin/+ and Pkhd1-/-;ApcMin/+ mice.
Conclution: Loss of Pkhd1 promotes the intestinal tumorigenesis and induces tumor malignant transformation in ApcMin/+ mice.
Citation Format: Bo Hu, Wei Li, Qingchao Qiu, Zhengxi He, Xiusheng He, Guanqing Wu. Loss of Pkhd1 promotes intestinal tumorigenesis in Apc mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3675.
Abstract 3679: Klotho suppresses colon cancer through modulation of the Wnt pathway and unfolded protein response
Authors: Rubinek Tami , Rubinstein Tammi , Shahmoon Shiri , Varol Chen , Zigmond Ehud , Rosin-Absesfelf Rina , Barshack Iris , Wolf Ido 
Published: July 2016

Abstract
Aberrant activation of the canonical Wnt pathway is implicated in colorectal cancer (CC) development and progression. β-catenin, the key effector of this pathway, functions with T-cell factor/lymphoid-enhancer-factor (TCF/LEF) to activate expression of Wnt target genes. Klotho is a transmembrane protein, which can be shed and act as a circulating hormone. Klotho-deficient mice manifest a syndrome resembling accelerated aging, while klotho overexpression extends life span. We previously identified klotho as a breast and pancreatic tumor suppressor (TS). Recent data indicate klotho as a TS in an array of malignancies, including CC. Among other activities, klotho inhibits the insulin-like growth factor (IGF)-1 and Wnt pathways. We aimed to decipher the role of klotho as a TS in CC.
We first noted that klotho overexpression inhibited CC cell colony formation. Next, we examined in vivo effects using the azoxymethane mouse model, and found that klotho inhibited colon polyp formation. We then used an orthotopic model by injecting MC38 cells to mice colons, and found that klotho inhibited colonic obstruction and tumor formation.
While we did not see an effect of klotho on the IGF-1 pathway, klotho did affect the Wnt pathway. Klotho reduced Wnt3A and β-catenin levels as measured by Western blotting, and inhibited TFC/LEF transcriptional activation in luciferase assay. As transcriptional inhibition was abrogated by a constitutively active β-catenin, we suspected that klotho inhibited the pathway upstream of β-catenin. Indeed, co-immunoprecipitation analyses indicated direct interaction between klotho and Wnt3A. As the inhibitory effect of klotho on CC cell colony formation was only partially rescued by a constitutively active β-catenin, additional mechanisms may be involved. Thus, we conducted a cDNA expression microarray and involvement of klotho in endoplasmic reticulum (ER) stress and unfolded protein response (UPR) was observed. Further studies showed that klotho induced elevation in XBP1 RNA, GRP78 protein levels, and eIF2α phosphorylation, all indicative of a role klotho plays in UPR regulation.
Our data indicate klotho as a potent TS in CC, and suggest its role at early stages of tumor formation. The Wnt pathway partially mediates klotho effects in CC, however additional mechanisms, including ER stress response regulation, are involved.
Citation Format: Tami Rubinek, Tammi Rubinstein, Shiri Shahmoon, Chen Varol, Ehud Zigmond, Rina Rosin-Absesfelf, Iris Barshack, Ido Wolf. Klotho suppresses colon cancer through modulation of the Wnt pathway and unfolded protein response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3679.
Abstract 3680: Loss of ARID1A expression leads to sensitivity to ROS-inducing agents in ovarian cancer cells
Authors: Kwan Suet-Yan , Wong Kwong-Kwok 
Published: July 2016

Abstract
AT-rich interactive domain-containing protein 1A (ARID1A) is frequently inactivated by mutations in a broad spectrum of cancer types, including ovarian and endometrial cancers. However, therapeutic strategies targeting ARID1A-mutant cancers remain limited. In this study, we aimed to identify drugs that selectively target ARID1A-mutant ovarian cancer cells. To this end, we compared the drug sensitivities of ARID1A-mutant and ARID1A-wildtype cancer cell lines using the Genomics of Drug Sensitivity in Cancer database. We found that ARID1A-mutant cancer cell lines were more sensitive to treatment with the reactive oxygen species (ROS)-inducing agent elesclomol compared to ARID1A-wildtype cancer cell lines. We validated this finding in a panel of ovarian and endometrial cancer cell lines, observing that treatment with elesclomol inhibited growth and induced apoptosis more potently in ARID1A-mutant cells than in ARID1A-wildtype cells. Knockdown of ARID1A expression in ARID1A-wildtype cells resulted in increased sensitivity to ROS-inducing agents, whereas re-expression of ARID1A in ARID1A-mutant cells resulted in decreased sensitivity. Finally, we found that knockdown of ARID1A expression resulted in increased intracellular ROS levels and subsequently promoted cell growth. In summary, we identified a novel role for ARID1A in protecting cells from oxidative stress and that ROS-inducing agents may be used to target ARID1A-mutant ovarian cancer cells.
Citation Format: Suet-Yan Kwan, Kwong-Kwok Wong. Loss of ARID1A expression leads to sensitivity to ROS-inducing agents in ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3680.
Abstract 3685: Redox regulation of p53 stability is a function of inhibition of PP2A-mediated dephosphorylation at threonine 55
Authors: Chong Stephen , Pervaiz Shazib 
Published: July 2016

Abstract
Protein Phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that has critical roles in numerous cellular pathways. The role of PP2A as an essential tumor suppressor in numerous death signaling pathways is well documented. In this regard, recent work from our laboratory has highlighted a novel mechanism of apoptosis inhibition via post-translational redox-modification of PP2A. Increase in intracellular superoxide, either by pharmacological inhibition or siRNA-mediated silencing of superoxide dismutase 1 (SOD1), results in the dissociation of PP2A-AC catalytic core from its B regulatory subunit. Dissociation of the PP2A heterotrimer is a result of the selective nitration [by peroxynitrite derived from the reaction of superoxide with nitric oxide] of a conserved tyrosine residue on B56δ which we identified as Y289 (B56δY289). Importantly, we showed in lymphoma cells that PP2A-AC catalytic core is typically targeted to Bcl-2 by its B56δ regulatory subunit. When O2- is elevated, it signals for the sustained phosphorylation of Bcl-2 at S70 by inducing the release of PP2A-AC catalytic core from B56δ-bound Bcl-2. This results in the sustained phospho-activation of anti-apoptotic Bcl-2 and resistance to apoptotic stimuli. Notably, Bcl-2 is not the only substrate of PP2A, nor is B56δ the only PP2A regulatory subunit susceptible to redox modification. Thus, implications from redox-modification of PP2A may extend beyond the phospho-activation of Bcl-2. In the context of carcinogenesis, another notable substrate of PP2A is the tumor suppressor, p53. p53 stability is negatively influenced by its phosphorylation status at threonine-55 (T55). Phosphorylation of T55, on the other hand, is countered by PP2A harboring the B56γ3 subunit. Here we provide evidence that the B56γ3 sub-unit of PP2A complexes with p53 and this complex is sustained upon an increase in intracellular superoxide. Importantly, redox-mediated inhibition of B56γ3-containing PP2A (PP2AB56γ3) prevents the dephosphorylation of p53 at T55, thereby negatively impacting the stability of p53 in tumor cells with elevated superoxide level. This, we hypothesize, may be a novel death inhibitory mechanism that renders tumor cells resistant to conventional DNA-damaging therapeutic agents that rely heavily on the activation of p53 for death induction.
Citation Format: Stephen Chong, Shazib Pervaiz. Redox regulation of p53 stability is a function of inhibition of PP2A-mediated dephosphorylation at threonine 55. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3685.
Abstract 3704: TRISENOX disrupts MDM2-DAXX-HAUSP interaction and increased promyelocytes formation in murine model of APL
Authors: Kumar Sanjay , Tchounwou Paul 
Published: July 2016

Abstract
Trisenox (ATO) is widely used in the treatment of all age group of acute promyelocytic leukemia (APL) patients in both induction and consolidation therapy. In vitro studies are shown that it works through oxidative stress, cell cycle regulation and apoptosis to kill APL cells having PML-RAR α oncogene. Some ATO resistant case of APL patients are reported with different oncogenes combination. However, in vivo anti-leukemic mechanism of action of ATO in APL patients poorly known. We have used transgenic murine model to elucidate the anti-cancer properties of ATO through new target. We hypothesized that ATO disrupts MDM2-DAXX-HAUSP interaction and also increased more number of promyelocytes formation inside bone marrow cells of APL mice. To test the hypothesis, we used different groups of younger (4-5weeks old) transgenic APL mice and standardized different dose of ATO (1.25, 2.5, 5.0 and 7.5 mg/kg body wt) after 21days continuous treatment in PBS. We utilized western blotting, immunocytochemistry, confocal imaging and other molecular techniques to identify molecular mechanisms of ATO action in APL mice hepatocytes as well as bone marrow cells. We found that it increases number of promyelocyte formation in bone marrow cells and also degradation of PML-RARα dose dependent fashion. ATO nicely activated p53 expression in both liver tissue as well as bone marrow cells of APL mice through degradation of MDM2. It was also disrupted both expression and association of MDM2-DAXX-HAUSP complex molecules dose dependent manner in mice liver tissues. On the basis of these findings, we conclude that ATO disrupts MDM2-DAXX-HAUSP interaction, increased promyelocytes formation, MDM2 degradation by accumulating P53 in APL mice liver tissues. It is novel target for treatment of APL patients through designing of new anti-leukemic drugs.
Keywords: Trisenox, P53, MDM2-DAXX-HAUSP complex molecules APL Mice hepatocytes and bone marrow cells.
Acknowledgements: This research was financially supported by National Institutes of Health NCRR Grant No. 5G12RR013459 and MIMHD Grant No. 8G12MD007581, through the RCMI-Center for Environmental Health at Jackson State University.
Citation Format: Sanjay Kumar, Paul Tchounwou. TRISENOX disrupts MDM2-DAXX-HAUSP interaction and increased promyelocytes formation in murine model of APL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3704.
Abstract 3713: Targeting alternative DNA repair pathways for cancer cell killing with heavy ion particles
Authors: Wang Huichen , Saganti Premkuma 
Published: July 2016

Abstract
Heavy ion therapy is a promising approach for cancer treatment, particularly for locally advanced solid tumors. High linear energy transfer (LET) radiation induces greater lesions density in close proximity (clusters) compared that in low-LET radiation. Such clustered DNA damage is thought to be more difficult to repair than isolated DNA damage produced by equivalent doses of low-LET radiation and persist longer in irradiated cells. It has been known that homologous combination contributes to the repair of clustered DNA damage other than classic non-homologous end-joining (NHEJ). DNA double-strand breaks are also repaired by an alternative NHEJ pathway with PARP1, DNA ligase III and Mre11. This alternative pathway is error prone and contributes to genomic instability, such as chromosomal translocation and telomere fusion. Genetic analysis of tumors in TCGA database revealed that these genes are amplified in human tumors and their overexpression is correlated with poor overall survival of cancer patients. However, influence of alternative NHEJ pathways on the relative biological effectiveness (RBE) of heavy ions remains unclear. Here we investigated the effect of PARP-1 and DNA ligase III on RBE of heavy ion particles on cell survival and chromosomal aberration in breast cancer cells and pancreatic cancer cells. Cells were irradiated with X-ray, Carbon (290 MeV/n, 13 KeV/μM) and Iron (1 GeV/n, 150 KeV/μM). We found that overexpression of PARP-1 and DNA ligase III increased RBE of carbon and iron. PARP inhibitor reduced chromosomal aberration induced by heavy ions. This study may provide predictor of radiation responsive of tumor cells from cancer patients that would lead to patient stratification for heavy ion therapy selection
Citation Format: Huichen Wang, Premkuma Saganti. Targeting alternative DNA repair pathways for cancer cell killing with heavy ion particles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3713.