bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4767: C6 ceramide sensitizes multiple aggressive pancreatic cancer cell lines to gemcitabine, paclitaxel and cetuximab mediated anti tumor effects in vivo and in vitro
Authors: Wanebo Harold J. , Lu Shan , Cong Cao , Shrayer David , Wan Yinsheng , Bowen Wayne 
Published: June 2012

Abstract
Introduction: Pancreatic adenocarcinoma continues to be a highly lethal malignancy (5 yr survival 5%) poorly responsive to all chemo radiation therapies, with only modest improvement with Gemcitabine the current “main line” drug. We have previously demonstrated the C6 Ceramide chemo enhancement of Gemcitabine and other pancreatic chemo agents. The current study explores the mechanism of C6 Ceramide effects on pancreatic chemo resistance pathways – pro-survival and ras-signaling in pancreatic cancer cells. Methods: In vivo: 2-3 month SCID male mice with pancreatic (pan) tumor implants (2 × 106 L3.6 cells) received intraperitoneal (I.P.) injections (3x/wk) of Paclitaxel (Pax) (3.0mg/gm), Gemcitabine (Gem, 10mg/gm) with/without C6 ceramide (10mg/ml) and were observed 6 weeks and tumor response/survival recorded. In vitro: Drug dose Pax 3 ug/ml, Gem 3 ug/ml, C6 Ceramide 10 ug/ml. The MTT anti tumor response was measured in 3 pancreatic lines L3.6, PANC-1, and MIA (Kras mutated). Signaling activation by Western blot utilized antibodies: LY294002, and Wortmannin to block PI3K/AKT pathway, U0126 and PD 98059 to block ERK pathway and Rapamycin to block mTORC1 pathway. Results: Combined therapy with C6 Ceramide induced significant inhibition of exponential tumor growth and prolonged survival by Gem and Pax. Administration of Gem or Pax with C6 Ceramide induced a significant increase in cell death and apoptosis in pancreatic cancer cells (L3.6, PANC-1 and MIA PaCa-2) which were associated with inhibiting perturbations of cell signaling pathways including pro-survival PI3K/Akt/mTOR, and ERK/MAPK, Ras signaling pathways. Pharmacological inhibition with specific signaling pathway inhibitors enhanced cytotoxicity by Gem or Pax, suggesting that survival pathway inhibition might be the key mechanism contributing to C6 Ceramide synergism of Pax or Gem anti-tumor effects. We also showed C6 ceramide potentiation of Cetuximab anti tumor effects on Kras mutant MIA cells thus overcoming (EGFR mAb) resistance by inhibiting pro-survival PI3K/AKT/mTOR pathways and bypassing K-RAS mutant Ras-ERK pathways. Conclusion: C6 Ceramide an apoptosis signal potentiates the anti tumor effects of chemo agents Gemcitabine and Paclitaxel and the biologic EGFR Inhibitor Cetuximab against 3 aggressive pancreatic cancer cell lines by apparent inhibition of the pro-survival PI3K/AKT/mTOR pathways and the Kras mutated ERK/MAPK 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 4767. doi:10.1158/1538-7445.AM2011-4767
Abstract 4770: TNFα and IFN-γ cooperate to up-regulate Fas expression to sensitize human colon carcinoma cells to Fas mediated apoptosis
Authors: Bardhan Kankana , Liu Kebin 
Published: June 2012

Abstract
Fas (also known as CD95) is a member of the tumor necrosis factor (TNF) superfamily that mediates the extrinsic apoptosis signaling pathway when engaged by its physiological ligand FasL. Although the Fas death receptor has been shown to initiate cellular proliferation and survival signal pathways in certain tumor cells uder certain conditions, it is generally believed that under physiological conditions Fas functions as a guardian against not only autoimmunity but also other disease including cancer. Fas is highly expressed in normal human colon epithelial cells but is often down-regulated in human colorectal carcinoma, whereas complete loss of Fas expression is often observed in metastatic human colorectal carcinoma. These observations thus suggest that colon carcinoma cells might use loss of Fas expression and/or function to acquire an apoptosis resistant phenotype to advance the disease. Therefore, re-activating Fas expression might be an effective approach to sensitize the human colon carcinoma cells to apoptosis to suppress tumor development. In this study, we demonstrated that there exist CpG islands in the human Fas promoter region and inhibition of DNA methylation up-regulates Fas expression in metastatic human colon carcinoma cells, resulting in increased tumor cell sensitivity to Fas-mediated apoptosis. However, bisulfite DNA sequencing revealed that there are just a few methylated CpGs in the human Fas promoter region in metastatic human colon carcinoma cells, suggesting that DNA methylation mediates Fas expression indirectly. On the other hand, TNFα and IFN-γ, when used in combination, dramatically up-regulated Fas expression level in the metastatic human colon carcinoma cells. Up-regulation of Fas by TNFα and IFN-γ also resulted in sensitization of the metastatic colon carcinoma cells to Fas-mediated apoptosis. Our data thus suggest that re-activation of the death receptor Fas might be an effective approach to enhance the efficacy of Fas-based therapy against metastatic human colon cancer.
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 4770. doi:10.1158/1538-7445.AM2011-4770
Abstract 4781: XIAP expression is associated with poor prognosis and is a promising therapeutic target for the treatment of papillary thyroid carcinoma
Authors: Hussain Azhar R. , Bavi Prashant , Bu Rong , Ahmed Maqbool , Al-Nuaim Abdulrehman , Ahmed Mohammed , Al-Sobhi Saif , Amin Tarek , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
The inhibitor of apoptosis protein (IAP) family member, X-linked Inhibitor of Apoptosis Protein (XIAP) is essential for cell survival in variety of cancers. However, the role of XIAP overexpression in papillary thyroid carcinoma (PTC) is not fully elucidated. Therefore, we analyzed the expression of XIAP protein and its clinico-pathological correlation in a large cohort of Middle Eastern PTC by immuno-histochemistry in a tissue micro-array format followed by in vitro studies using PTC cell lines. XIAP was found to be over-expressed in 25% of PTC and directly associated with older age (p&lt;0.0001) and presence of extra-thyroidal extension (p&lt;0.0001). Interestingly, XIAP was also found to be significantly associated with tall-cell variant (p=0.0013), larger tumor size (p=0.0002) and advanced stage (III and IV) disease (p&lt; 0.0001). XIAP over-expression was also significantly associated with over-expression of oncogenic c-Met (p=0.0010) and anti-apoptotic Bcl-Xl protein (p&lt;0.0001). Finally, PTC with XIAP over-expression showed a significantly poor disease free survival (p=0.0476) of 63.1 months as compared to the PTC's with low XIAP expression (74.0 months). Our in vitro data showed that embelin, a selective inhibitor of XIAP, caused a dose dependent inhibition of cell proliferation in PTC cell lines. Furthermore, we found that embelin induced a dose dependent apoptosis as detected by cell cycle analysis and annexin V/PI dual staining in PTC cells. On further analysis, our data showed that embelin induced a caspase-dependent apoptosis of PTC cells via activation and cleavage of capsases-9 and -3 and cleavage of PARP. In summary, our clinical data highlights the fact that XIAP over-expression in PTC confer a aggressive phenotype with poor outcome. In vitro studies using XIAP inhibitor suggest that this sub-group of PTC with over-expression of XIAP can be therapeutically targeted to induce efficient apoptosis in these cancers.
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 4781. doi:10.1158/1538-7445.AM2011-4781
Abstract 4782: The NEDD8-activating enzyme inhibitor, MLN4924, cooperates with TRAIL to augment apoptosis through JNK-dependent downregulation of c-FLIP in head and neck cancer cells
Authors: Zhao Liqun , Yue Ping , Lonial Sagar , Khuri Fadlo R. , Sun Shi-Yong 
Published: June 2012

Abstract
The death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is a tumor-selective cytokines with potential anticancer activity and is currently being tested in clinical trials. Like other types of cancers, head and neck squamous cell carcinoma (HNSCC) cells posses varied sensitivity to TRAIL. MLN4924 is a newly developed small molecule inhibitor of NEDD8-activating enzyme with potent anticancer activity. Elevated NEDD8 conjugation has been reported in HNSCC cells. However, the effects of MLN4924 on the growth of HNSCC cells and on TRAIL-induced apoptosis in HNSCC cells have not been evaluated. In this study, we showed that MLN4924 effectively inhibited the growth of HNSCC cells (IC50s &lt; 0.4 μM) with potent apoptosis-inducing activity. Moreover, MLN4924 synergized with TRAIL to decrease the survival and to induce apoptosis of HNSCC cells. Interestingly, MLN4924 decreased c-FLIP levels with minimal effects on DR4 and DR5 expression. Enforced expression of c-FLIP substantially attenuated MLN4924/TRAIL-induced apoptosis. These data indicate that c-FLIP reduction plays an important role in mediating cooperative induction of apoptosis by the MLN4924 and TRAIL combination. Furthermore we found that MLN4924 decreased c-FLIP stability, increased c-FLIP ubiqutination and facilitated c-FLIP degradation, suggesting that MLN4924 decreases c-FLIP levels through promoting its degradation via an ubiqutination and proteasome-dependent mechanism. Additionally, MLN4924 potently activated JNK signaling evidenced by increased levels of phospho-c-Jun in MLN4924-treated cells. Blockage of the JNK activation with the JNK inhibitor SP600125 not only prevented MLN4924-induced c-FLIP reduction, but also inhibited MLN4924/TRAIL-induced apoptosis. These results suggest that JNK activation mediates c-FLIP downregulation and subsequent enhancement of TRAIL-induced apoptosis induced by MLN4924. Our findings thus warrant further evaluation of the efficacy of MLN4924 or its combination with TRAIL against the HNSCC in vivo and highlight a novel mechanism by which MLN4924 modulates apoptosis. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award, Department of Defense VITAL W81XWH-04-1-0142 and NIH/NCI Head and Neck Cancer SPORE CA128613 awards. FR Khuri and SY Sun are Georgia Cancer Coalition Distinguished Cancer Scholars)
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 4782. doi:10.1158/1538-7445.AM2011-4782
Abstract 4784: Targeting NF-kappaB pathway with Bay11-7085 leads to inhibition of cell viability and induces apoptosis in primary effusion lymphoma cells
Authors: Hussain Azhar R. , Ahmed Maqbool , Ahmed Saeeda O. , Bu Rong , Khan Omar S. , Platanias Leonidas , Al-Kuraya Khawla S. , Uddin Shahab 
Published: June 2012

Abstract
Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin's B cell lymphoma that mainly grows as a lymphomatous effusion in body cavities and is infected with Kaposi sarcoma-associated herpesvirus (KSVH/HHV8). A number of constitutively activated signaling pathways play critical role in the survival and growth of PEL cells including NF-kB. NF-κB is constitutively activated in a number of cancers including multiple myeloma, burkitt's lymphoma and diffuse large B-cell lymphoma. However, its role in primary effusion lymphoma has not been fully explored. Therefore, in this study, we found that Bay11-7085, an inhibitor of NF-kB pathway inhibit cell viability and induce apoptosis in several PEL cell lines in a dose dependent manner. Such effects of Bay11-7085 result from its ability to in-activate p-IκBα leading to the inability of p65 subunit of NF-κB to enter the nucleus to assert its anti-apoptotic transcriptional activity. Our data demonstrate that Bay11-7085 treatment of PEL cell lines causes de-phosphorylation of Bad protein leading to conformational changes of Bax protein and subsequently translocation from cytosole to mitochondria causing loss of mitochondrial membrane potential with subsequent release of cytochrome c from the mitochondria. Released cytochrome c into the cytosole activates caspases-9 and -3, followed by polyadenosin-5’-diphosphate-ribose polymerase (PARP) cleavage. In addition, pretreatment of PEL cells with zVAD-fmk, a universal inhibitor of caspases prevents caspase-3 activation and abrogates cell death induced by Bay11-7085 treatment of PEL cells strongly suggesting that Bay11-7085-induced apoptosis is caspase dependent. Finally, treatment of PEL cells with Bay11-7085 down-regulates the expression of inhibitor of apoptosis proteins (IAP). Altogether, these data suggest that NF-κB plays an important role in PEL cell survival and targeting this pathway with Bay11-7085 induces caspase dependent apoptosis via disruption of mitochondrial pathway. This raises the possibility that this agent may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of the NF-κB 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 4784. doi:10.1158/1538-7445.AM2011-4784
Abstract 4785: Silver nanoparticles induce apoptosis in squamous lung cancer cell by regulation of cyclic AMP response element-binding protein: regulating its upstream oxidative stress-dependent Ras signaling pathways
Authors: Park Hee Sun , Jang Sunhyae , Cha Hye Rim , Jeong Sun Young , Lee Jeong Eun , Kim Ju Ock , Koo Ja Seok , Kim Sun Young 
Published: June 2012

Abstract
Recently, much effort has been devoted to the development of biomedical applications (drug delivery system and as therapeutic drugs themselves) for nanoparticles (NPs). Silver NPs have been shown various therapeutic effects such as antimicrobial, antioxidant, and anti-inflammatory effects. Recently silver NPs have been shown to induce cytotoxicity in cancer cells. But exact mechanism is not yet established. We conducted this study to determine the mechanisms of silver NPs on cellular apoptosis in non-small cell lung cancer (NSCLC) cell lines using cyclic AMP response element-binding protein (CREB) activity which has been implicated to contribute an important pathobiologic role in lung carcinogenesis and is considered a potential therapeutic target for NSCLC. We hypothesized that constitutively increased CREB and its related signaling pathways can be blocked by silver NPs and it might be by regulation of oxidative stress in tumorigenesis. In H520 cell, human lung squamous cancer cell line, reactive oxygen species (ROS) were increased. In western blot analysis, Ras signaling molecule in which ROS is involved was constitutively overexpressed and the levels of pErk, pRsk, pAkt and pCREB were increased in H520 cell. Incubation of the H520 cells with silver NPs (at dose of 100 or 200 μM) substantially suppressed the ROS in H520 cell and Ras-Erk-Rsk-CREB and Ras-PI3K-Akt signaling pathway in a dose-dependent manner. We subsequently demonstrated that silver NPs inhibited the caspase-dependent pathway, determined by increased levels of PARP (poly (ADP-ribose) polymerase) cleavage. In this study, we suggest that silver NPs induce apoptosis in human lung cancer cells by attenuation of oxidative stress in lung cancer cell line and ROS-dependent Ras signaling which involves CREB signaling pathways and may be useful as a therapeutic strategy for cancer.
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 4785. doi:10.1158/1538-7445.AM2011-4785
Abstract 4787: MMP-2 RNA interference leads to decreased NF-κB activation and induced JNK-mediated apoptosis by modulating TRADD-TRAF2-FADD interactions in glioma
Authors: Kesanakurti Divya , Chetty Chandramu , Bhoopathi Praveen , Lakka Sajani S. , Gorantla Bharathi , Tsung Andrew J. , Rao Jasti S. 
Published: June 2012

Abstract
MMP-2 belongs to a family of extracellular matrix metalloproteinases (MMPs) that play a pivotal role in the degradation of the ECM, thereby enhancing the invasive and metastatic potential of cancer cells. Our study unveiled a new mechanism of how MMP-2 RNA interference inhibits NF-κB activation. Essentially, siRNA against MMP-2 (pM) modulated the interactions between the adaptor protein TRADD-TRAF2 and TRADD-FADD, which consequently hindered the nuclear localization and DNA binding activity of NF-κB. This, in turn, led to apoptosis. Furthermore, pM treatment led to RIP cleavage and remarkable increases in the expression levels of FADD and activated MAP kinases, p38 MAPK and JNK. The prolonged activation of JNK resulted in phosphorylation of c-Jun. Treatments with specific JNK1 inhibitor (SP600125) reduced and significantly reversed the pro-apoptotic effect of pM, thereby suggesting a role of JNK in pM-induced cell death. Supplementation of recombinant human MMP-2 to pM-transfected cells restored the inhibited DNA binding activity of NF-κB and rescued cells from the pro-apoptotic effect of pM. Here, we demonstrate that the simultaneous inhibition of NF-κB activation and sustained activation of JNK play significant roles in pM-mediated apoptosis in human xenograft glioma cells. In addition, our results show that the specific downregulation of MMP-2 diminished intracranial tumor growth in vivo. The inhibition of tumor growth after pM treatment was associated with decreased MMP-2 expression, inhibited NF-κB activation, and enhanced phospho-JNK levels. In conclusion, the present study elucidates an underlying mechanism of pM-induced cell death in vitro as well as decreased tumor development in vivo.
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 4787. doi:10.1158/1538-7445.AM2011-4787
Abstract 4788: Protein kinase CK2 modulates TAp73 phosphorylation and suppresses apoptosis in head and neck cancer
Authors: Lu Hai , Brown Matthew , Hu Michael , Unger Gretchen , Van Waes Carter , Chen Zhong 
Published: June 2012

Abstract
The TP53 family member TAp73 has been shown to be pro-apoptotic and enhance chemosensitivity, but is inactivated in head and neck squamous cell carcinoma (HNSCC). We recently found that the inflammatory cytokine, TNFα, induces NF-κB activation and TAp73 nuclear export, which contribute to the suppression of TAp73 pro-apoptotic function. However, the intermediate signaling involved in TNFα regulated TAp73 inactivation and modulation of apoptosis has not been defined. Here, we found that TAp73 exhibits varying levels of phosphorylation in a panel of HNSCC cell lines. An inverse association between phospho- and total TAp73 protein expression was observed, suggesting that signal phosphorylation could contribute to TAp73 turnover. In response to TNFα treatment, phosphorylated TAp73 decreased in the nucleus while increasing in the cytoplasm, consistent with nuclear-cytoplasmic translocation. As we previously showed that protein kinase CK2 subunits are aberrantly overexpressed and promote IKK-NF-κB activation in HNSCC, we examined CK2 as a potential upstream regulator of TAp73 phosphorylation. Both CK2 inhibitor DMAT (2-Dimethy-lamino-4,5,6,7-tetrabromo-1H-benzimidazole) and CK2α siRNA inhibited TAp73 phosphorylation, as well as increased TAp73 mRNA and protein expression. Consequently, DMAT treatment increased the expression of TAp73 downstream pro-apoptotic genes, p21, PUMA and NOXA through increased TAp73 binding to the promoters of these genes. DMAT treatment and mutation of TAp73 phosphorylation sites increased p21 reporter activity. Furthermore, DMAT blocked cell cycle progression and proliferation, and increased apoptosis of HNSCC in vitro. Delivery of anti-CK2α/α′ oligodeoxy-nucleotide nanocapsules into HNSCC xenograft models significantly suppressed tumor growth, concomitant with decreased TAp73 phosphorylation, increased expression of TAp73, and target apoptotic proteins PUMA and NOXA. These results suggest that the aberrant activation of protein kinase CK2 could be one of the upstream signaling molecules modulating phosphorylation of TAp73, TAp73 nuclear exportation, and suppression of apoptosis in HNSCC cells.
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 4788. doi:10.1158/1538-7445.AM2011-4788