bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 208: The function of p53 is intact in murine basal cell carcinomas in IR-treated Ptch1+/- mice
Authors: Wang Grace Y. , Wang Joy , Wang Lynn , Libove Eileen , Epstein Ervin H. 
Published: July 2012

Abstract
Basal cell carcinomas (BCC) are the most common cancer among people of European ancestry. Although mutational activation of Hedgehog (HH) signaling is pivotal for BCC carcinogenesis, p53 mutations also frequently are present in human and mouse BCCs. In humans, these p53 mutations are frequently of a “UV-signature” type, and human BCCs typically arise in sun-damaged skin containing epidermal clones of p53 mutant cells, implying that p53 is a crucial BCC tumor suppressor. In line with this notion, we found that deletion of p53 specifically in K14-expressing keratinocytes dramatically accelerates BCC carcinogenesis in ionizing radiation (IR)-treated Ptch1+/- mice. In IR-treated Ptch1+/- mice without p53 deletion, visible BCCs can also arise from but with longer tumor latency (9m vs. 5m) and a lower tumor incidence (10% vs. 100%) and mutiplicity. However it is not known whether loss of p53 signaling activity is required for the development of visible BCCs in p53+/+ mice. To address this question, we compared p53 signaling activity in IR-induced BCCs in Ptch1+/- p53+/+ mice vs. in BCCs in Ptch1+/- p53-/- mice after a second, DNA-damaging dose of IR. Using immunohistochemistry, we found the expected minimal IR-induced expression of p53, Puma, and Noxa as well as TUNEL-detected apoptosis in BCCs of p53-deleted mice. By contrast, IR induced robust expression of p53, Noxa, Puma, and apoptosis in BCCs from Ptch1+/- p53-intact mice. Without IR exposure, BCCs in p53+/+ mice had scattered p53+ cells and low level of expression of Puma and Noxa but no TUNEL+ cells. Our data thus suggest that IR-induced BCCs generated in Ptch1+/- p53+/+ mice retain their functional p53 signaling capacity and that these tumors are able to evade an intact DNA damage response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 208. doi:10.1158/1538-7445.AM2011-208
Abstract 2081: The unfolded protein response relieves stress in tumor cells by stimulating angiogenesis
Authors: Wang Yugang , Ning Yu , Alam Goleeta , Visioli Fernanda , Nör Jacques E. , Polverini Peter J. 
Published: July 2012

Abstract
Abstract: During the avascular phase, tumor size is limited to 1-2 mm in diameter. When tumors exceed this size, the high stress imposed by limited glucose and oxygen in the microenvironment induces the unfolded protein response (UPR). Previous studies have shown that the UPR can promote survival, or activate apoptosis when there is prolonged or severe stress. Recent studies have suggested a role for the UPR in angiogenesis. However, the mechanism of UPR-regulated angiogenesis has not been extensively investigated. We hypothesize that tumor cells relieve stress caused by nutrient and oxygen deprivation by stimulating blood vessel growth via UPR-mediated induction of angiogenesis. To address this hypothesis, a human squamous cell carcinoma line, UM-SCC-81B, was subjected to glucose deprivation and mRNA array was used to evaluate expression of UPR proteins and angiogenesis mediators. This study revealed an increase in expression of several UPR proteins (Grp78, DDIT3, ATF3, ATF4, ATF6) ranging from 2 to 20-fold after 24 hours of glucose deprivation (0.1 mM glucose), and a 4.43, 3.06 and 2.59-fold increase in the expression of the pro-angiogenic VEGF, FGF2 and IL-6, respectively. Western blot, ELISA and q-PCR were used to verify these results. Western blot analysis showed a significant increase of Grp78 and DDIT3 protein expression. ELISA experiments revealed that after 24 hours of glucose deprivation, VEGF levels increased 3 folds as compared to the non-treated control, and that FGF2 and IL-6 were also upregulated (p &lt; 0.05). q-PCR results further revealed that UPR markers (Grp78, DDIT3, ATF4) and angiogenesis mediators (VEGF, FGF2, IL-6) increased significantly (p &lt; 0.05). Four other tumor cell lines (i.e. U87, glioma; MCF7, breast cancer; UM-SCC 11B and UM-SCC 17B, head and neck squamous carcinomas) were examined to determine the cell-type specificity of these responses. In all tumor cell lines examined, the upregulation of UPR proteins was associated with a significant increase in VEGF expression (p &lt; 0.05). In conclusion, the UPR response is associated with the upregulation of critical pro-angiogenic factors in tumor cell lines. These data strongly suggest that targeting pathways involved in UPR regulation of angiogenesis is a promising strategy in combination with other conventional cancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2081. doi:10.1158/1538-7445.AM2011-2081
Abstract 2084: Reactive oxygen species activate the IRE1-XBP1 pro-apoptotic pathway by recruiting TRAF2 to IRE1 and activating an IRE1-TRAF2-JNK pathway in human glioma cells
Authors: Kim Yeon Hyang , Koh Hyung-Kon 
Published: July 2012

Abstract
To investigate the function of the oxidative stress in the endoplasmic reticulum (ER) -related cell death of glioma, the human glioma cells were treated with hydrogen peroxide, TNF, and thapsigargin to raise intracellular levels of hydroxyl radical and ER stress, respectively. Hydrogen peroxide and thapsigargin increased cytosolic Ca2+, induced the activation of caspase 3, and caused apoptosis in a dose-dependent manner. In contrast, TNF affect neither cell viability nor the increase of cytosolic Ca2+. Both hydrogen peroxide and thapsigargin increased the expressions of ER-associated molecules including p-PERK, IRE1-α, p-eIF, ATF-1, p-CREB and Ero1-α in human glioma cells, whereas TNF did not increase the expressions of them. Hydrogen peroxide and thapsigargin increased IRE1-α nuclease activity generating transcriptionally active form of XBP-1 and induced IRE1-α-TRAF2 complex formation which initiates JNK activation and increase of expressions of p-JNK1 and p-JNK2. On the other hand, TNF-α did not increase p-JNK1and p-JNK 2 levels. IRE1-α induction coincided with those of p-JNK1, p-JNK and induced formation of IRE1-α-TRAF2 in hydrogen peroxide- and thapsigargin- treated cells. Therefore, we conclude that the increase of expression of IRE1-α is necessary for activating TRAF2-JNK pathway and causing oxidative stress- induced cell death of glioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2084. doi:10.1158/1538-7445.AM2011-2084
Abstract 209: Zinc is essential for the efficacy of p53 reactivating drugs
Authors: Azmi Asfar S. , Sukari Ammar , Philip Philip A. , Mohammad Ramzi M. 
Published: July 2012

Abstract
According to the International Zinc Nutrition Consultative Group, 20% of the world's population lack sufficient Zinc in their diet. Zinc is required by &gt;200 different proteins including the most extensively studied Zinc-finger protein p53 that is considered guardian of genome. Its crucial role in p53 core domain folding has been proven, as disruption of this interaction greatly reduces or abrogates p53 DNA binding and transactivation of target genes. Therefore, alterations in Zinc homeostasis may impair p53 activity and also reduce the efficacy of wt-p53 re-activating drugs. Recently, we have shown that Zinc is necessary for proper wt-p53 re-activation and cancer cell apoptosis by small molecule inhibitors of HDM2 such as MI-219 (Oncogene 2010). As a logical extension to our these results, in this clinically translatable study we show that Zinc is crucial for the activity of mutant p53 reactivated by PRIMA and provide evidence for using combination therapies with PRIMA that include supplemental Zinc for the treatment of mut-p53 tumors. ZnCl2 (64 µM) enhanced PRIMA (0-100 µM) anti-tumor activity (induced growth inhibition and apoptosis and suppressed colony formation) in multiple pancreatic, colon and breast cancer cell lines. Chelation of Zinc by chelex 100 resin not only blocked the activity of PRIMA, but also suppressed reactivation of the mut-p53 and its downstream effector molecules 14-33σ, Bax and p21 as detected by western blot analysis. N,N,N'N′-tetrakis(−)[2-pyridylmethyl]-ethylenediamine (TPEN), a specific Zinc chelator, but not 1,2-bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (Bapta-AM), a calcium chelator or desferroxamine, a iron chelator blocked PRIMA-induced apoptosis. Zinc chelation by TPEN suppressed p53 nuclear localization that is important for its transcriptional activity. Zinc did not affect PRIMA activity in p53 null cells, suggesting that this was indeed a p53 dependent phenomenon. Addition of Zinc suppressed the known p53 feedback MDM2 activation, which could be restored by TPEN. Before wt- or mut-p53 re-activating drugs such as MI-219 and PRIMA make their way into the clinic for cancer patients who usually have mild to moderate Zinc deficiency, we believe that the results of our findings will help in the design of novel combination strategies with Zinc for better survival outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 209. doi:10.1158/1538-7445.AM2011-209
Abstract 2094: Hsp70 inhibitors overcome tamoxifen resistance, in cell culture model
Authors: Koren John , Miyata Yoshinari , Kiray Janine , Guo Jianping , Gestwicki Jason , Cheng Jin Q. , Dickey Chad 
Published: July 2012

Abstract
A prevalent problem in the use of chemotherapies for the treatment of human cancers is the potential for the development of resistance. While the exact nature of the mechanisms involved in resistance development vary based on cancer type as well as the nature of the therapeutics; some oncogenic factors have been established to have roles in the desensitization to common treatments. Previous data from our lab demonstrated Hsp70 inhibitors can reduce Akt levels. a major proliferation and survival factor also linked to estrogen receptor therapeutic based resistance. We have, Uusing these Hsp70 ATPase-inhibiting compounds and ain a cell culture model of tamoxifen resistant breast cancer, we have identified compounds which can re-sensitize resistant cells. These compounds inhibit cytosolic and mitochondrial members of the 70-kDA heat-shock protein family. These compounds also reduce Akt levels, a major proliferation and survival factor also linked to estrogen receptor therapeutic based resistance, as well as Thus, in addition to reducing Akt levels and possibly other oncogenic chaperone clients, these drugs may also interrupt mitochondrial function leading to reduced viability in the presence of tamoxifen. With these mechanisms in mind, we now have data that Ttamoxifen resistant MCF7 cells regained sensitivity to tamoxifen after brief treatments with Hsp70-family inhibitors. The resistant cells were grown in media containing tamoxifen. This media was replaced with media containing an Hsp70 inhibitor compound for four hours. After the four hours, the Hsp70 inhibitor media was removed and tamoxifen-containing media was reapplied to the cells. Multiple viability and cytotoxicity assays confirm the drop in viability and increased cytotoxicity following these treatments. These studies demonstrate that Hsp70 family members are potentially valuable targets for new cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2094. doi:10.1158/1538-7445.AM2011-2094
Abstract 2097: ARHI (DiRAS3): A novel component in the formation of the autophagy initiation complex
Authors: Lu Zhen , Liao Warren S. , Yang Maojie , Gao Fengqin , Bast Robert 
Published: July 2012

Abstract
The maternally imprinted Ras-related tumor suppressor gene Aplasia Ras homolog member I (ARHI; also known as DiRAS3) is downregulated in more than 60% of ovarian cancers. We reported that re-expression of ARHI in vitro at physiologic levels induces autophagy by blocking PI(3)K-Akt signaling and inhibiting mTOR activity, and participates directly in the autophagic vesicles, co-localizing with MAP-LC3-II in the vesicle membrane. Nucleation of autophagic vesicles is controlled by the activity and formation of multi-protein complexes that include Beclin-1 and several other positive and negative regulators. While binding of Beclin-1 to Vps34 and ATG14 forms proautophagic complexes to promote autophagy, binding of Bcl-2 to Beclin-1, however, disrupts the Beclin-1:Vps34 interaction and inhibits autophagy. The mechanisms that regulate the switch between different binding partners to Beclin-1, and therefore controls the level of autophagy is not clear. Here we report that ARHI physically interacts with endogenous Beclin-1 and Vps34 in ovarian cancer cells. Interaction with ARHI decreases the association between Beclin-1 and its negative regulator Bcl-2, by disrupting Beclin-1 homodimerization. An N-terminal deletion of ARHI that cannot induce autophagy fails to block Beclin-1 homodimerization and cannot disrupt Beclin-1:Bcl-2 interaction. Consistent with its role in promoting the formation of autophagy initiation complex, cells with knockdown of ARHI fail to respond to starvation-mediated dissociation of Beclin-1:Bcl-2 interaction and are unable to induce Beclin-1:Vps34 complex formation. Finally, ARHI knockdown decreases PI(3)KC3 activity and reduces starvation-mediated autophagy. Taken together, our results suggest that ARHI is a positive and necessary regulator of Beclin-1:Vps34 complex and that ARHI regulates starvation-mediated autophagy by promoting the formation of the autophagy initiation complexes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2097. doi:10.1158/1538-7445.AM2011-2097
Abstract 210: Metastasis-associated protein 1 is a transcriptional target of the tumor suppressor p53
Authors: Na Hyelin , Lee Min-Ho , Kim Kyu-Seo , Lee Jung Weon , Lee Mi-Ock 
Published: July 2012

Abstract
Although metastasis-associated protein 1 (MTA1) is known to play roles in angiogenesis and metastasis in various human cancers, the molecular mechanism of regulation of MTA1 gene expression remains unclear. Therefore, we searched potential regulators of MTA1 expression in this study. Treatment of 5-fluorouracil (5-FU), a traditional anti-cancer drug in HepG2, MCF7 and LNCaP cells, expressing wild-type p53, decreased the protein and mRNA expression of MTA1. However, the MTA1 expression levels were not altered in response to 5-FU treatment in Hep3B, MDA-MB-231 and PC3 cells which lack functional p53. The specific knockdown of p53 in HepG2 and MCF7 cells recovered the level of MTA1 after 5-FU treatment. This observation indicates that p53 mediates the repression of MTA1. Next, we virtually analyzed the promoter region of the human MTA1 gene and identified several potential consensus binding sequences of p53. Indeed, chromatin immunoprecipitation and pull-down assays showed that p53 directly bound to the MTA1 promoter region. These findings suggest that p53 is transcriptionally associated with regulation of MTA1 gene expression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 210. doi:10.1158/1538-7445.AM2011-210
Abstract 2100: Role of pocket proteins in HPV-associated head and neck squamous cell carcinomas
Authors: Shin Myeong Kyun , Pitot Henry C. , Sage Julien , Lambert Paul F. 
Published: July 2012

Abstract
High-risk human papillomaviruses(HPVs) are associated with a subset of head and neck squamous cell carcinomas (HNSCC) as well as most of cervical cancers. HPV type 16 (HPV-16), which is found in the vast majority of HPV-positive HNSCC, encodes for three oncogenes: E5, E6, and E7. Previously, we learned that HPV-16 E7 is the dominant oncoprotein in head and neck cancer in mice. More recently, we learned that tissue specific inactivation of the retinoblastoma-susceptibility gene, pRb, a well known cellular target of HPV E7 and a member of the “pocket protein’ family, was not sufficient to account fully for the oncogenic properties of E7 in HNSCC. E7 is known to inactivate not just pRb, but also other related cellular proteins, specifically p107 and p130. This led to our current study in which we have observed that the combined loss of pRb and p130, or pRb and p107 leads to increased susceptibility to head and neck cancers in comparison to mice conditionally disrupted only for pRb, yet are not sufficient to account fully for E7's oncogenic potential in HPV-associated head and neck carcinogenesis. Additionally, combinatorial loss of pRb and p130, or pRb and p107 partially mediates E7-induced acute phenotypes in head and neck epithelia. Taken together, our results indicate that the combined inactivation of two pocket proteins are not sufficient to fully recapitulate E7 oncogenic properties in HNSCC. We conclude that inactivation of all three pocket proteins is necessary to account for E7's carcinogenic properties in HNSCC or that other targets of E7 contribute to its carcinogenic potential in HNSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2100. doi:10.1158/1538-7445.AM2011-2100
Abstract 2106: The role of KSRP in non-small cell lung cancer
Authors: Wilson Lora A. , Winn Robert A. 
Published: July 2012

Abstract
Precedent has established the role of the Wnt/β-catenin pathway in oncogenesis. Several members of the Wnt family are known to be tumor promoting in non-small cell lung cancer, NSCLC. In this pathway β-catenin, a downstream component, accumulates and serves as a T-cell transcription /lymphoid enhancer factor. We previously identified the Wnt ligand in the lung, Wnt 7a, as a member of the non-canonical pathway/ β-catenin independent pathway, which inhibits transformed cell growth. Currently, we hypothesize that the regulatory protein, KSRP, holds a switch between the canonical and non-canonical pathway. K-homology splicing regulatory protein (KSRP) is a member of the family of AU rich element binding proteins. It possesses four K-homology motifs and causes decay of specific mRNA transcripts in different cell types. In mouse F9 teratocarcinoma cells KSRP negatively regulates β-catenin. The role of KSRP in the non-canonical Wnt pathway in the lung has previously been unknown. Using NSCLC cell lines and nontransformed lung cells we show a correlation between Wnt 7a expression and a positive regulation of KSRP. KSRP expression is elevated in nontransformed cells and alternatively, lower levels of KSRP expression in NSCLC. Over expression of KSRP in NSCLC cells decreases cell proliferation in MTS assay as well as reducing colony formation in clonogenic assays. The silencing of KSRP in nontransformed cells results in an increase in cell proliferation. The positive regulation of KSRP by Wnt 7a positively regulates this mRNA regulatory protein in the noncanonical Wnt pathway as an important factor in tumor suppression. The canonical pathway negatively regulates KSRP, which allows the stabilization of β-catenin mRNA thereby promoting progression of the tumor-promoting pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2106. doi:10.1158/1538-7445.AM2011-2106
Abstract 2113: Programmed cell death 4 (PDCD4) regulates apoptotic resistance of human gliomas
Authors: Liwak Urszula , Jordan Lindsay , Holcik Martin 
Published: July 2012

Abstract
Glioblastoma multiforme (GBM) is the most prevalent form of tumors of the central nervous system with an average survival rate of less than one year. Given the location and characteristics of GBM only limited treatment options are available, thus understanding the mechanisms of GBM formation or progression may lead to the development of novel treatment options. Strikingly, a common feature of GBM is the loss of expression of the tumor suppressor programmed cell death gene 4 (PDCD4), which correlates with a poor prognosis. Through both transcriptional and translational regulation, PDCD4 has been shown to regulate many proteins within the cell, although the precise mechanism of target selection is not known. We have hypothesised that silencing of PDCD4 in glioblastomas leads to an altered expression of apoptosis-regulating proteins resulting in the suppression of apoptotic signals and enhanced chemo-resistance of glioblastomas. Indeed, we show that low levels of PDCD4 correlate with an increase in the anti-apoptotic XIAP and Bcl-xL proteins, and decrease in pro-apoptotic Apaf-1. Importantly, these proteins are regulated at the level of protein synthesis through the internal ribosome entry sites (IRESs) in the 5’ untranslated region (UTR) of their respective mRNAs. IRES elements allow for translation to occur through a cap-independent mechanism during times of cellular stress when global translation is attenuated. We further show that PDCD4 regulates the activity of Bcl-xL, XIAP and Apaf-1 IRES and is therefore an IRES specific translational regulator. We further dissect the signalling pathways that regulate PDCD4 levels and show that activation of S6K2 results in the proteolytic degradation of PDCD4 and concomitant upregulation of XIAP and Bcl-xL, and downregulation of Apaf-1 levels. Importantly, reintroduction of PDCD4 into glioblastoma cell lines results in a reduction in both XIAP and Bcl-xL protein levels and enhanced cell death. In summary, our work provides a novel role for PDCD4 as a translational regulator of XIAP, Bcl-xL and Apaf-1, as well as a mechanistic understanding into the regulation of PDCD4 expression. Our research offers insight into the biology of glioblastomas in the hopes that we can identify new pathways as novel targets for anticancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2113. doi:10.1158/1538-7445.AM2011-2113