bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2268: Suicidal tendencies: The promotion of cell death by a prolactin antagonist through autophagy in ovarian cancer
Authors: Wen Yunfei , Zand Behrouz , Yu Kang , Bottsford-Miller Justin , Stone Rebbeca L. , Carroll Amy , Pecot Chad V. , Pradeep Sunila , Wu Sherry , Hu Wei , Ozpolat Bulent , Coleman Robert , Sood Anil K. 
Published: August 2012

Abstract
As a multifunctional pituitary hormone and cytokine, prolactin (PRL) is not only essential for normal reproduction and maintenance of pregnancy, but is involved in over 300 biological activities. There is increasing evidence that PRL plays a role in a variety of cancers including ovarian cancer. Elevated levels of PRL have been reported in patients with ovarian cancer. Furthermore, increased expression of PRL receptors (PRLr) have been shown in ovarian cancers, signifying the importance of PRL-mediated signaling in ovarian carcinogenesis. Abnormal activities of PRLr-mediated signaling pathways such as MAPK and JAK2/STAT5 lead to tumorigenicity and recurrence. Therefore, inhibition of PRL signaling is implicated as a target in cancer therapy; however, no viable strategies have been identified for blocking PRL during tumor progression. Herein, we report a novel strategy to counteract the activity of PRLr-mediated cellular survival in malignant ovarian cancer cells with autophagic cell death. Prolanta (G129R), an analog of human PRL with a single amino-acid substitution at position 129 Glycine with bulky Arginine, induces adaptive autophagy through antagonism of the PRLr expressed on human ovarian cancer cells (HeyA8 and SKOV3). The mouse ovarian cancer cell IG10, which does not express PRLr, had no induction of autophagy upon Prolanta treatment. We also identified that Prolanta competitively binds to PRLr and partially inhibits the oncogenic signaling pathways mediated by PRLr, including JNK/STAT3, PI-3K/Rac/PAK pathways that can lead to cell proliferation, differentiation and survival. In addition, we observed cell death after Prolanta treatment in 3-D-spheroid models. We explored molecular mechanisms behind this autophagic cell death induced by Prolanta. Through biomarker identification using the reverse phase protein array (RPPA), we revealed a signaling complex regulated by Pea-15, an autophagy activator through JNK-pathway, which was activated by Prolanta. Microarray analysis reported an array of autophagic genes activated by Prolanta. Furthermore, in an orthotopic mouse model, Prolanta treatment with or without a taxane caused significant inhibition of SKOV3 and HeyA8 growth. In summary, Prolanta functions as a molecular antagonist to tumor-associated PRL by inducing adaptive autophagic cell death in human ovarian cancer. These preclinical findings reveal the novelty of Prolanta as an adjuvant therapy for ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2268. doi:1538-7445.AM2012-2268
Abstract 2269: Lapatinib and obatoclax kill cns tumor cells through blockade of erbb1 / 3 / 4 and through inhibition of bcl-xl and mcl-1
Authors: Cruickshanks Nichola A. 
Published: August 2012

Abstract
Previous studies in breast cancer cells have shown that Lapatinib (Lap) and Obatoclax (GX) interact in a greater than additive manner to cause cell death. The present studies sought to expand our analyses to CNS (Glioblastoma & Medulloblastoma) tumor cells and to further advance our understanding of the mechanisms of drug action. Combinational treatment with Lap / GX resulted in enhanced tumor cell death in multiple CNS tumor types. Moreover, it was discovered that cells lacking PTEN function were resistant to drug combination lethality and re-expression of PTEN in PTEN null cells restored drug sensitivity. Furthermore, PTEN expressing cancer cells, sensitive to Lap / GX treatment, demonstrated drug resistance upon knockdown of PTEN. Additionally, we established that inhibition of ERBB1 / 3 / 4 receptors was most significant for enhancing GX lethality, and that knockdown of BCL-XL and particularly MCL-1, interacted to facilitate Lap lethality. Pre-treatment of tumor cells in vitro and in vivo with GX enhanced the lethality of Lap to a greater extent than concomitant treatment and suppressed tumor growth. Treatment of animals carrying orthotopic CNS tumor isolates and those implanted with anoikis resistant breast tumors in the brain with Lap / GX prolonged survival. Collectively our data argues that combinational Lap / GX therapy could be of use in the treatment of tumors located in the CNS. Further studies must be carried out in order to elucidate whether autophagy or apoptosis plays the most predominant role in cell death in response to Lap / GX treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2269. doi:1538-7445.AM2012-2269
Abstract 2271: Autophagy induction by low dose cisplatin: The role of p53 in autophagy
Authors: Yang Sei-Hoon , Lee Kang Kyoo , Moon Sun Rock 
Published: August 2012

Abstract
Cisplatin has been mainly used for lung-cancer. However, cisplatin has many side effects, so the usage of cisplatin has a limitation. Recently, autophagy has become an important mechanism of cell death. The purpose of this study was to determine whether low dose cisplatin treated lung cancer cell induce autophagy and the autophagy inhibition resulted in apoptosis or necrosis. H460 cells were treated with 5 μM or 20 μM cisplatin for 12, 24, or 48 h. To detect the cisplatin-induced autophagy, we examined the autophagic vacuoles, and LC3 localization. To confirm the low-dose of cisplatin could induce autophagy, we detectd acidic vesicle using autophagy specific inhibitors(3-MA). To confirm the result of autophagy inhibition, we had done Annexin-V/PI and cell cycle assay. To find out the cisplatin mediated autophagic mechanisms, we examined the apoptotic regulator, p53. We used p53-/- null cancer cell line, H1299, to prove the role of p53 during autophagy. Low dose of cisplatin(5 μM) induced the autophagy after 24 h treatment in H460. Also low dose of cisplatin showed autophagic vacuoles and cytoplasmic LC3 formation in H460. The induction of autophagy by low dose cisplatin was inhibited by 3-MA, which was proven by reduced acidic vesicles. When the autohpagy inhibited, Annexin-V+/PI- and subG1 was an increased. The inhibition of autophagy resulted in decrease of LC3B-II band. Also cleaved caspase-3 and PARP were increased. Taken together, low dose cisplatin induced autophagy and the inhibition of autophagy resulted in the apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2271. doi:1538-7445.AM2012-2271
Abstract 2272: Heme oxygenase-1 regulates apoptosis and autophagy for the survival of renal cancer cells
Authors: Banerjee Pallavi , Basu Aninda , Wegiel Barbara , Otterbein Leo E. , Choi Augustine M. K. , Pal Soumitro 
Published: August 2012

Abstract
Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation pathway is classically known for its cytoprotective role during tissue injury. However, this protective function of HO-1, which is essential for maintaining cellular homeostasis under stress conditions, may act as a double-edged sword by promoting survival of cancer cells. HO-1 is overexpressed in different cancers, and cancer cells may utilize the anti-apoptotic effects of HO-1 as a shield against chemotherapeutic agents. We have recently demonstrated that activation of the oncogenic Ras pathway induces HO-1 to promote survival of renal cancer cells. Recent studies show that along with apoptosis, type II cell death or autophagy also plays a vital role in regulating the fate of cancer cells. While some groups suggest that toxic autophagy cooperates with chemotherapeutic agents to facilitate apoptosis of cancer cells, others propose a protective role of autophagy in cancer. Here, we investigated whether HO-1 can control apoptosis- and autophagy-related genes to regulate survival of human renal cancer cells (786-0 and Caki-1). We overexpressed HO-1 in these cells either by CoPP treatment, a known inducer of HO-1, or by transfecting the cells with a human HO-1 overexpression plasmid. We observed that the overexpression of HO-1 increased the level of anti-apoptotic protein Bcl-xL as observed by Western blot analysis; and this was associated with a significant decrease in the expression of autophagic proteins Beclin-1 and LC3B-II. The knockdown of HO-1 using specific siRNA led to down-regulation of Bcl-xL, and a marked increase in LC3B-II expression. Moreover, we found that the treatment of renal cancer cells with either rapamycin or sorafenib (two commonly used drugs for the treatment of renal cancer) induced the protein expression of HO-1; and apoptotic effects of these drugs on cancer cells were markedly enhanced in presence of the HO-1 inhibitor SnPP as observed by FACS analysis using Annexin-V staining. Together, our results indicate that HO-1 is up-regulated in renal cancer cells for their survival against chemotherapeutic agents, and it may protect the cells from both apoptosis- and autophagy-mediated death. Besides, recent studies demonstrated that both rapamycin and sorafenib can induce autophagy. Considering this together with our data, we suggest that application of these drugs along with HO-1 inhibitor may result in more efficient killing of renal cancer cells by reducing cytoprotective effects of HO-1 and by simultaneous induction of both autophagy and apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2272. doi:1538-7445.AM2012-2272
Abstract 2273: Autophagic cell death induced by curcumin is mediated by p38/Beclin 1 to crosstalk with apoptotic cell death in DU145 cells
Authors: Kang Dongxu , Park Wungki , Kim Joo-Hang , Song Jae Jin 
Published: August 2012

Abstract
Curcumin as an anticancer agent was investigated to study how it can regulate cancer cells’ destination to either apoptosis or autophagy. At higher concentration, curcumin induced ROS production leading to JNK and p38 phosphorylation in DU-145 prostate cancer cell. Of the two MAP kinases, p38 was phosphorylated earlier during curcumin treatment, and responsible for curcumin-induced autophagic cell death by using GFP-LC3 expression. p38-induced autophagy signaling pathway occurred at even 1h, and was enhanced by blocking JNK signaling, and JNK signaling was more involved in apoptosis rather than autophagy. In the case of curcumin treatment. Beclin 1, an essential autophagic protein was mainly activated by dissociation from Bcl2 or Bcl-xL after Beclin 1 phosphorylation induced by p38-DAPK, or from Bcl-2 phosphorylation induced by JNK1. Based on these results, we concluded that curcumin exhibited cytotoxicity in DU-145 cells and this cytotoxicity was mediated by p38 signaling pathway triggering both beclin 1 activation to induce autophagic cell death, which in turn inhibits the apoptotic cell death induced by curcumin-ROS-JNK signaling cascade, leading to a complex crosstalk between autophagy and apoptosis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2273. doi:1538-7445.AM2012-2273
Abstract 2276: Coordinate autophagy and PI3K/Akt/mTOR pathway inhibition enhances cell death in melanoma
Authors: Xie Xiaoqi , Mehnert Janice M. , White Eileen P. 
Published: August 2012

Abstract
The PI3K/Akt/mTOR pathway is a critical survival pathway in numerous malignancies, including melanoma. Inhibitors of this pathway in cancer cells, in particular mTOR, are commonly cytostatic rather that cytotoxic, which may potentially limit efficacy of these agents. mTOR inhibition also induces the survival pathway of autophagy, a catabolic process whereby cells collect and recycle cellular components to sustain energy homeostasis. Thus we tested the hypothesis that autophagy induction by mTOR inhibitors directly limited their efficacy for the treatment of melanoma. Here we found that melanoma exhibits high basal levels of autophagy, as evidenced by a) detection of autophagosomes using LC3 fluorescence and autophagic flux in multiple melanoma cell lines and b) increased LC3 fluorescence in human primary and metastatic melanomas compared to benign nevi. Knockdown of Atg7, a key element of autophagy machinery, resulted in cell death, indicating that survival of melanoma cells is autophagy dependent. We also showed that the autophagy inhibitor hydroxychloroquine (HCQ) shows synergy when combined with the mTOR inhibitor CCI-779 (temsirolimus), inducing cell death via increased apoptosis in melanoma cell lines and in 3-D spheroid cell cultures. Since autophagy eliminates mitochondria that are a source of toxic reactive oxygen species (ROS) and mediators of apoptosis, we tested the possibility that this contributed to melanoma survival. To test this potential mechanism, we examined the role of the transcription factor Nrf2, a master regulator of antioxidant defense. Treatment with CCI-779 inactivated Nrf2 by blocking its nuclear translocation and creating the requirement for autophagy to eliminate ROS-producing mitochondria. Combination treatment with CCI-779 and HCQ then prevented mitochondrial elimination by autophagy, resulting in increased ROS production compared to either agent alone and increased cell death. Conversely, knockdown of the Nrf2 binding protein and inhibitor Keap1 increased Nrf2 activity, resulting in increased cell culture survival and resistance to treatment with CCI-779 and HCQ. These data suggest that coordinate inhibition of the PI3K/Akt/mTOR and autophagy pathways promotes ROS-mediated apoptosis and is a new therapeutic paradigm for the treatment of melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2276. doi:1538-7445.AM2012-2276
Abstract 2281: Signaling from lysosomes to mitochondria sensitizes head and neck cancer cells to photodynamic treatment: Role of mitoferrin 2
Authors: Hung Hsin-I , Lemasters John J. , Nieminen Anna-Liisa 
Published: August 2012

Abstract
Photodynamic therapy (PDT) involves activation by light of a photosensitizer in a tissue, resulting in singlet oxygen formation and cell death. The aim of this study was to investigate the interactions between lysosomes and mitochondria in promoting PDT killing of head and neck cancer cells. Three head and neck cancer cell lines (UMSCC1, UMSCC14 and UMSCC22) were subjected to PDT with Pc 4, a mitochondria-targeted photosensitizer. After comparable Pc 4-PDT, cell killing was greater in UMSCC22 than UMSCC1 or UMSCC14 cells. Pc 4-PDT caused 85% cell killing in UMSCC22 cells compared to 20% killing in UMSCC1 or UMSCC14 cells. In non-erythroid cells, mitoferrin 2 (Mfrn2) is an iron transporter in the mitochondrial inner membrane, and PDT-sensitive UMSCC22 cells expressed &gt;5 times higher Mfrn2 protein levels compared to PDT-resistant UMSCC1 and UMSCC14 cells as determined by Western blotting. Bafilomycin, an inhibitor of the vacuolar proton pump of lysosomes and endosomes enhanced Pc 4-PDTcytoxicity. Mfrn2 protein overexpression in low Mfrn2 expressing cells enhanced sensitivity to Pc 4-PDT plus bafilomycin. Conversely, knocking down (90% knock down) Mfrn2 by siRNA decreased cells’ sensitivity to the Pc 4-PDT plus bafilomycin treatment. Iron chelators (desferrioxamine and starch-desferrioxamine) and the inhibitor of the mitochondrial calcium (and ferrous iron) uniporter, Ru360, protected against PDT plus bafilomycin treatment from Pc 4- mitochondria-mediated cell killing. In conclusion, the data suggest that lysosomal iron release and mitochondrial iron uptake through Mfrn2 act synergistically to induce PDT-induced cell killing. Furthermore, Mfrn2 represents a possible biomarker in predicting efficacy of the PDT treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2281. doi:1538-7445.AM2012-2281
Abstract 2287: Inhibition of microRNA-32 leads to decreased expression of the survival-enhancing scaffold protein hKSR2 in human myeloid leukemia cells treated with vitamin D derivatives
Authors: Wang Xuening , Chen-Deutsch Xiangwen , Harrison Jonathan S. , Studzinski George P. 
Published: August 2012

Abstract
1,25-dihydroxyvitamin D3 (1,25D) has potential for treatment and/or prevention of human AML by inducing terminal differentiation of AML cells to monocyte-like phenotype, but the mechanisms underlying this action are not fully understood. We hypothesized that one or more microRNAs (miRNAs) known to control mouse hematopoiesis and lineage commitment may contribute to the known ability of 1,25D to control the malignant phenotype. We found that miR181a and miR32 both participate in the differentiating effects of 1,25D, with effects on cellular levels of cell cycle regulator p27Kip1 and the pro-apoptotic protein Bim, respectively. Here we report that in human AML cells modulation of 1,25D-induced expression of miR32 and miR181a can result in the down-regulation of the abundance of the scaffold protein hKSR2, which is associated with inhibition of differentiation. This supports the concept that hKSR2 is under miRNA control in AML cells. However, ectopic expression of miR32 had little effect on hKSR2 protein levels, suggesting that there is an indirect effect of miR32 on hKSR2 expression, and that intracellular levels of the intermediary regulators are already at saturation levels. Since hKSR2 protein has cell survival-enhancing properties, 1,25D-induced miRNAs and hKSR2 changes may reduce the therapeutic efficacy of 1,25D and analogs in human AML, especially when vitamin D analogs are combined with conventional cytotoxic anti-leukemia agents. This warrants consideration in the design of clinical trials. (This research was supported by NIH grant R01 CA 044722-22 from the National Cancer Institute).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2287. doi:1538-7445.AM2012-2287
Abstract 229: Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase non-receptor type 14
Authors: Zhang Peng , Wang Zhenghe 
Published: August 2012

Abstract
Protein tyrosine phosphatases (PTPs) are thought to be potentially important regulators in tumorigenesis as antagonists of protein tyrosine kinases (PTKs). Among them, Protein tyrosine non-receptor type 14 (PTPN14) has been shown to be mutated in both colorectal and breast cancers. However, little is known about the cellular signaling pathways it regulates. In order to determine whether PTPN14 has causative roles in tumorigenesis, we set out to identify substrates of PTPN14 and shed light on the mechanism why it is mutated in different tumor types. In this study, we report the identification of p130Cas, a scaffolding molecule, as a substrate of PTPN14 through a proteomic approach. We show that PTPN14 specifically dephosphorylates p130Cas at tyrosine 128 by shRNA knockdown and overexpression. We also demonstrate p130Cas is a direct substrate of PTPN14 by substrate trapping and in vitro phosphatase assays. We then mutate tyrosine 128 residue to phenylalanine in DLD1 and RKO, two different colorectal cell lines, to study the biological functions of this phosphosite. The mutant cells show reduced tumorigenicity based on colony formation and soft agar assays. However, the phenotypes diverge between the mutant cells from the two cell lines when we test the effect of the mutation on tumor growth in xenograft model. RKO Y128F mutant cells display significantly reduced tumor volumes while DLD1 Y128F mutant cells do not. In addition, RKO Y128F mutant cells are less invasive than parental cells in Matrigel but DLD1 Y128F mutant cells are surprisingly more invasive. We find that AKT is not fully activated in both mutant cells, which is likely the cause of the common phenotypes. However, phospho-ERK is up-regulated in DLD1 mutant cells possibly due to a compensatory mechanism but not in RKO mutant cells since ERK is already constitutively active in RKO cells, which explains the discrepancies in phenotypes mentioned above. Last, Src is shown to be the kinase of p130Cas Y128. When the phosphorylation of p130Cas Y128 is surveyed in six commonly used colorectal cancer cell lines, the phosphorylation levels are found to be correlated with the sensitivities to Src inhibitor. Thus, p130Cas Y128 phosphorylation can be utilized as a prognostic marker for Src inhibitors that are already in clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 229. doi:1538-7445.AM2012-229