Survival Factor For Cancer Cells Research Articles

SITP: A single cell bioinformatics analysis flow captures proteasome markers in the development of breast cancer

Single cell sequencing and related databases have been widely used in the exploration of cancer occurrence and development, but there is still no in-depth explanation of specific and complicated cellular protein modification processes. Ubiquitin-Proteasome System (UPS), as a specific and precise protein modification and degradation process, plays an important role in the biological functions of cancer cell proliferation and apoptosis. Proteasomes, vital multi-catalytic proteinases in eukaryotic cells, play a crucial role in protein degradation and contribute to tumor regulation. The 26S proteasome, part of the ubiquitin–proteasome system. In this study, we have enrolled a common SITP process including analysis of single cell sequencing to elucidate a flow that can capture typical proteasome markers in the oncogenesis and progression of breast cancer. PSMD11, a key component of the 26S proteasome regulatory particle, has been identified as a critical survival factor in cancer cells. Results suggest that PSMD11’s rapid degradation is linked to acute apoptosis in cancer cells, making it a potential target for cancer treatment. Our study explored the potential mechanisms of PSMD11 in breast cancer development. The findings revealed the feasibility of disclosing ubiquitinating biomarkers from public database, as well as presented new evidence supporting PSMD11 as a potential therapeutic biomarker for breast cancer.

ATO Increases ROS Production and Apoptosis of Cells by Enhancing Calpain-Mediated Degradation of the Cancer Survival Protein TG2.

Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.

SLU7: A New Hub of Gene Expression Regulation-From Epigenetics to Protein Stability in Health and Disease.

SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.

The transglutaminase 2 cancer cell survival factor maintains mTOR activity to drive an aggressive cancer phenotype.

Transglutaminase 2 (TG2) is an important cancer stem-like cell survival protein that is highly expressed in epidermal squamous cell carcinoma and drives an aggressive cancer phenotype. In the present study, we show that TG2 knockdown or inactivation results in a reduction in mammalian target of rapamycin(mTOR) level and activity in epidermal cancer stem-like cells which are associated with reduced spheroid formation, invasion, and migration, and reduced cancer stem cell and epithelial-mesenchymal transition(EMT) marker expression. Similar changes were observed in both cultured cells and tumors. mTOR knockdown or treatment with rapamycin phenocopies the reduction in spheroid formation, invasion, and migration, and cancer stem cell and EMT marker expression. Moreover, mTOR appears to be a necessary mediator of TG2 action, as a forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and cancer stem cell and EMT marker expression. Tumor studies show that rapamycin reduces tumor growth and cancer stem cell marker expression and EMT. These studies suggest that TG2 stimulates mTOR activity to stimulate cancer cell stemness and EMT and drive aggressive tumor growth.

Melatonin and doxorubicin synergistically enhance apoptosis via autophagy-dependent reduction of AMPK\u03b11 transcription in human breast cancer cells

Doxorubicin is one of the most effective agents used to treat various cancers, including breast cancer, but its usage is limited by the risk of adverse effects, including cardiotoxicity. Melatonin, a natural hormone that functions as a major regulator of circadian rhythms, has been considered a supplemental component for doxorubicin due to its potential to improve its effectiveness. However, the mechanisms and biological targets of the combination of melatonin and doxorubicin with respect to cancer cell death are not well understood. In the present study, we found that melatonin synergized with doxorubicin to induce apoptosis of breast cancer cells by decreasing the expression of AMP-activated protein kinase α1 (AMPK α1), which acts as a critical survival factor for cancer cells. This cotreatment-induced reduction in AMPKα1 expression occurred at the transcriptional level via an autophagy-dependent mechanism. The synergistic effects of the combined treatment were evident in many other cancer cell lines, and melatonin was also highly effective in inducing cancer death when combined with other cancer drugs, including cisplatin, 5-fluorouracil, irinotecan, and sorafenib. AMPKα1 expression was decreased in all of these cases, suggesting that reducing AMPKα1 can be considered an effective method to increase the sensitivity of cancer cells to doxorubicin treatment.

Generation and identification of a conditional knockout allele for the PSMD11 gene in mice

BackgroundOur previous study have shown that the PSMD11 protein was an important survival factor for cancer cells except for its key role in regulation of assembly and activity of the 26S proteasome. To further investigate the role of PSMD11 in carcinogenesis, we constructed a conditional exon 5 floxed allele of PSMD11 (PSMD11flx) in mice.ResultsIt was found that homozygous PSMD11 flx/flx mice showed normal and exhibited a normal life span and fertility, and showed roughly equivalent expression of PSMD11 in various tissues, suggesting that the floxed allele maintained the wild-type function. Cre recombinase could induce efficient knockout of the floxed PSMD11 allele both in vitro and in vivo. Mice with constitutive single allele deletion of PSMD11 derived from intercrossing between PSMD11flx/flx and CMV-Cre mice were all viable and fertile, and showed apparent growth retardation, suggesting that PSMD11 played a significant role in the development of mice pre- or postnatally. No whole-body PSMD11 deficient embryos (PSMD11−/−) were identified in E7.5–8.5 embryos in uteros, indicating that double allele knockout of PSMD11 leads to early embryonic lethality. To avoid embryonic lethality produced by whole-body PSMD11 deletion, we further developed conditional PSMD11 global knockout mice with genotype Flp;FSF-R26CAG − CreERT2/+; PSMD11flx/flx, and demonstrated that PSMD11 could be depleted in a temporal and tissue-specific manner. Meanwhile, it was found that depletion of PSMD11 could induce massive apoptosis in MEFs.ConclusionsIn summary, our data demonstrated that we have successfully generated a conditional knockout allele of PSMD11 in mice, and found that PSMD11 played a key role in early and postnatal development in mice, the PSMD11 flx/flx mice will be an invaluable tool to explore the functions of PSMD11 in development and diseases.

PRMT6 deficiency induces autophagy in hostile microenvironments of hepatocellular carcinoma tumors by regulating BAG5-associated HSC70 stability.

Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis by degrading damaged organelles and unwanted proteins and supports cellular biosynthesis in response to stress. Cancer cells, including hepatocellular carcinoma (HCC), are often situated in a hypoxic, nutrient-deprived and stressful microenvironment where tumor cells are yet still able to adapt and survive. However, the mechanism underlying this adaptation and survival is not well-defined. We report deficiency of the post-translational modification enzyme protein arginine N-methyltransferase 6 (PRMT6) in HCC to promote the induction of autophagy under oxygen/nutrient-derived and sorafenib drug-induced stress conditions. Enhanced autophagic flux in HCC cells negatively correlated with PRMT6 expression, with the catalytic domain of PRMT6 critically important in mediating these autophagic activities. Mechanistically, PRMT6 physically interacts and methylates BAG5 to enhance the degradation of its interacting partner HSC70, a well-known autophagy player. The therapeutic potential of targeting BAG5 using genetic approach to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC is also demonstrated in an in vivo model. The clinical implications of these findings are highlighted by the inverse correlative expressions of PRMT6 and HSC70 in HCC tissues. Collectively, deficiency of PRMT6 induces autophagy to promote tumorigenicity and cell survival in hostile microenvironments of HCC tumors by regulating BAG5-associated HSC70 stability through post-translational methylation of BAG5. Targeting BAG5 may therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to sorafenib for treatment.

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target.

Transglutaminase 2 (TG2) has emerged as a key cancer cell survival factor that drives epithelial to mesenchymal transition, angiogenesis, metastasis, inflammation, drug resistance, cancer stem cell survival and stemness, and invasion and migration. TG2 can exist in a GTP-bound signaling-active conformation or in a transamidase-active conformation. The GTP bound conformation of TG2 contributes to cell survival and the transamidase conformation can contribute to cell survival or death. We present evidence suggesting that TG2 has a role in human cancer, summarize what is known about the TG2 mechanism of action in a range of cancer types, and discuss TG2 as a cancer therapy target.

Abstract 1349: Functional and mechanistic characterization of PRMT6 regulated autophagy in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is a major health burden worldwide. Tumor recurrence and therapy resistance represent major obstacles in the treatment of the disease, with their mechanism of action largely uncharacterized. Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis including degradation of damaged organelles and unwanted proteins as well as the support of cellular biosynthesis in response to environmental stress, preventing cells from undergoing apoptosis. Our group has recently reported on the regulatory role of protein arginine methyltransferase 6 (PRMT6) down-regulation in maintenance of HCC, particularly potentiating resistance to sorafenib and chemotherapy. By tandem affinity purification/mass spectrometry analysis of cells with PRMT6 stably overexpressed, we identified a number of autophagy related proteins as potential interacting partners of PRMT6, suggesting a possible role of PRMT6 in modulating autophagy in HCC. Treatment of HCC cells with stress induced conditions, including sorafenib, nutrient deprivation and hypoxic condition, resulted in a marked reduction of PRMT6 expression, concomitant with elevated levels of LC3BII. Further, under these various stimuli, knockdown of PRMT6 in HCC cells would also result in enhanced expression of LC3BII, accumulation of GFP-LC3B positive puncta staining as well as an increase in autophagosome formation. Consistently, treatment of HCC cells with PRMT6 overexpressed would leading to an opposing effect. Further studies by immunoprecipitation analysis validated PRMT6 to physically interact with AMBRA1 (activating molecule in BECN1-regulated autophagy protein 1), a well-known autophagy initiative component, which takes part in autophagy vesicle nucleation, a critical step for autophagic initiation. Our findings suggest PRMT6 down-regulation in HCC tumors to promote tumorigenicity through autophagic flux de-regulation. Targeting the mechanisms of stress response may provide novel therapeutic insights for the disease. Citation Format: Noélia Che, Man Tong, Kai Yu Ng, Phillis WF Kau, Xin Yuan Guan, Michael SY Huen, Stephanie Ma. Functional and mechanistic characterization of PRMT6 regulated autophagy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1349.

SAT-425 - SLU7 is a survival factor for cancer cells working as a mitotic regulator

SAT-425 - SLU7 is a survival factor for cancer cells working as a mitotic regulator

Transglutaminase is a tumor cell and cancer stem cell survival factor.

Recent studies indicate that cancer cells express elevated levels of type II transglutaminase (TG2), and that expression is further highly enriched in cancer stem cells derived from these cancers. Moreover, elevated TG2 expression is associated with enhanced cancer stem cell marker expression, survival signaling, proliferation, migration, invasion, integrin-mediated adhesion, epithelial-mesenchymal transition, and drug resistance. TG2 expression is also associated with formation of aggressive and metastatic tumors that are resistant to conventional therapeutic intervention. This review summarizes the role of TG2 as a cancer cell survival factor in a range of tumor types, and as a target for preventive and therapeutic intervention. The literature supports the idea that TG2, in the closed/GTP-binding/signaling conformation, drives cancer cell and cancer stem cell survival, and that TG2, in the open/crosslinking conformation, is associated with cell death.

The role of CD95 and CD95 ligand in cancer.

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.

OP17 Cystathionine-β-synthase (CBS) is upregulated in colorectal cancer cells and promotes their proliferation

OP17 Cystathionine-β-synthase (CBS) is upregulated in colorectal cancer cells and promotes their proliferation

Abstract 852: Novel role and mechanism of the LDHA protein as a survival factor for cancer cells.

Abstract Rationale: Lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate, serves as a poor prognostic serum marker for many different types of human cancers; however, it is not known whether this is simply the result of LDHA being released from dying cancer cells in patients with high tumor burden or whether LDHA could also be a signaling molecule that portends poor clinical outcome. Based on the observation that extracellular LDHA was identified as the key survival factor for cardiomyocytes exposed to oxidative stress, we sought to determine whether extracellular LDHA can act as a cancer cell survival factor and hence contributes to poor clinical outcome. We reasoned that LDHA released from the damaged cells could activate intracellular signaling pathways in surrounding tumor cells by means of membrane receptors, ultimately protecting those surrounding tumor cells from oxidative stress-induced cell death. Methods: To investigate our hypothesis, recombinant LDHA and its isoform LDHB was produced by transforming E. coli strain BL21(DE3) with pET-SUMO expression vector (Clontech) containing full-length human LDHA or LDHB cDNA. The resulting recombinant proteins were purified using TALON Metal Affinity Resin and used for 16h pre-treatment of Ramos human Burkitt's lymphoma and A6L human pancreatic cancer cells cultured in full serum containing medium. The amount of recombinant proteins relative to serum albumin is estimated to be less 1% and hence any effects of LDHA could not be simply due to non-specific protein concentration effect. Following the pre-treatment procedure, these cancer cells were subjected to oxidative stress induced by hydrogen peroxide (H2O2) at 100 μM for 24h. Cells were then counted in a hemacytometer using trypan blue dye to exclude dead cells. Results: We observed that while LDHB had no effect on cell death induced by H2O2 as compared to the non-pretreatment group, LDHA can act as a protective factor against oxidative stress induced by H2O2, and ultimately cell death. We also investigated the mechanism involved in the protective role of LDHA by using recombinant LDHA as a molecular probe against membrane proteins that were extracted from cancer cells. Conclusion: Our study defines the novel role and mechanism of LDHA protein as a survival factor in cancer cells, in addition to its enzymatic activity, which may explain the prognostic significance of extracellular LDHA. Furthermore, this study can lead to the identification of new membrane receptor(s) for LDHA which may provide new targets for cancer therapy. Citation Format: Brad Poore, Joshua Kee Park, Iman Afif, Laura Shingleton, Chi Van Dang, Anne Le. Novel role and mechanism of the LDHA protein as a survival factor for cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 852. doi:10.1158/1538-7445.AM2013-852

Abstract LB-205: The calcium activated chloride channel ANO1 promotes breast cancer progression by activating EGFR- and CAMK-signaling.

Abstract Genomic alterations are the underlining cause of many human cancers: Amplified and overexpressed genes can drive neoplastic transformation and become essential survival factors for cancer cells. Thus, they represent promising targets for anti-cancer therapies and their identification and validation is of paramount importance. In a search for novel survival factors contributing to breast cancer oncogenesis, we performed genomic fine mapping of the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human neoplasia, in a large dataset of breast cancer patients. Remarkably, we found ANO1, a calcium-activated chloride channel, to be located within the summit of the most frequently and highly amplified genomic region. Furthermore, amplification of ANO1 correlates with its overexpression and elevated protein levels and is a negative predictor for overall survival in breast cancer patients. Next, we examined how ANO1 contributes to cancer cell survival and proliferation. We found that inhibition of ANO1 expression or function reduced cancer cell viability and colony formation, and triggered apoptosis in 11q13 amplified breast cancer, HNSCC and ESCC. Furthermore, expression of ANO1 in non-transformed mammary cells increased cell viability and established a novel addiction to ANO1 biochemical activity. We next applied inducible shRNAs against ANO1 in vivo to assess the effect of ANO1 inhibition on the maintenance of established tumors. We found in four different 11q13-amplified tumor models that knockdown of ANO1 reduced tumor growth, indicating an important role for ANO1 not only in oncogenesis, but also in tumor maintenance of 11q13 amplified cancers. To explore the mechanism by which inhibition of ANO1 contributes to cancer cell viability and tumor growth, we performed antibody arrays to measure the activity of major oncogenic signaling pathways after knockdown of ANO1. Upon depletion of ANO1, activation of EGFR and several survival signaling pathways (AKT-, SRC- and ERK1/2 pathways) were reduced in different models of human cancer. Subsequent experiments showed that ANO1 modulates both EGFR- and Ca2+/calmodulin-dependent protein kinase (CAMK) signaling in breast cancer and HNSCC cells. Consistently, activation of EGFR- and CAMK correlated with the expression of ANO1 in human primary breast tumor samples. Lastly, we found that only the simultaneous stimulation of EGFR- and CAMK-signaling pathways rescued the effect of the ANO1-inhibition. In summary, our study establishes ANO1 as a key tumor-promoting factor in 11q13-amplified breast and other malignancies. Our results highlight the importance of chloride channels in cancer and provide the first detailed mechanistic insight into the activity of ANO1 in tumorigenesis. Most importantly, our findings open up new opportunities for therapeutic intervention in several prevalent cancers. Citation Format: Adrian Britschgi, Anke Bill, Heike Brinkhaus, Christopher Rothwell, Ieuan Clay, Stephan Duss, Michael Rebhan, Pichai Raman, Chantale Guy, Kristie Wetzel, Elizabeth George, M. Oana Popa, Sarah Lilley, Hedaythul Choudhury, Martin Gosling, Louis Wang, Stephanie Fitzgerald, Jason Borawski, Jonathan Baffoe, Mark Labow, L. Alex Gaither, Mohamed Bentires-Alj. The calcium activated chloride channel ANO1 promotes breast cancer progression by activating EGFR- and CAMK-signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-205. doi:10.1158/1538-7445.AM2013-LB-205

Identification of the Cancer Cell Proliferation and Survival Functions of proHB-EGF by Using an Anti-HB-EGF Antibody

PurposeHeparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the epidermal growth factor family. The membrane-bound proHB-EGF is known to be a precursor of the soluble form of HB-EGF (sHB-EGF), which promotes cell proliferation and survival. While the functions of sHB-EGF have been extensively studied, it is not yet fully understood if proHB-EGF is also involved in cellular signaling events. In this study, we utilized the anti-HB-EGF monoclonal antibodies Y-142 and Y-073, which have differential specificities toward proHB-EGF, in order to elucidate proHB-EGF functions in cancer cells.Experimental DesignThe biological activities of proHB-EGF were assessed in cell proliferation, caspase activation, and juxtacrine activity assays by using a 3D spheroid culture of NUGC-3 cells.ResultsY-142 and Y-073 exhibited similar binding and neutralizing activities for sHB-EGF. However, only Y-142 bound to proHB-EGF. We could detect the function of endogenously expressed proHB-EGF in a 3D spheroid culture. Blocking proHB-EGF with Y-142 reduced spheroid formation, suppressed cell proliferation, and increased caspase activation in the 3D spheroid culture of NUGC-3 cells.ConclusionsOur results show that proHB-EGF acts as a cell proliferation and cell survival factor in cancer cells. The results suggest that proHB-EGF may play an important role in tumor progression.

Abstract 5106: Autophagy in malignant melanoma and breast carcinoma

Abstract We show here for the first time that autophagy is a remarkably common characteristic of malignant melanomas and breast carcinomas and is highly associated with metastasis and poor patient outcome. Autophagy is a cytoplasmic degradative process that in cancer can provide an energy source in times of nutrient deprivation. Interest in autophagy and cancer progression has increased markedly in recent years with reports that autophagy can be both a positive and negative survival factor for cancer cells. PURPOSE. The purpose of this study was to evaluate the prevalence of autophagy in melanoma and breast carcinoma, cancers from tissues of dissimilar lineages and functions. METHODS. Standard biopsies and tumor tissue microarrays containing core samples of melanoma (n = 342 cases) or breast carcinoma (n = 611 cases) were stained by immunohistochemistry for the autophagosome marker LC3B (microtuble-associated protein light chain 3B, detected with anti-LC3B polyclonal antibody ab48394, Abcam, Inc., Santa Cruz, CA). Autophagy was verified by the LC3B granular staining pattern and, in melanoma, by electron microscopy. RESULTS. In standard biopsies of melanoma, autophagic tumor cells emerged sporadically within the in situ tumor and were apparently the source of invasive cells in the dermis. For melanoma microarrays, 82% (107/130) of primary invasive melanomas and 90% (189/212) of lymph node metastases showed nearly uniform expression of autophagy with metastases showing increased LC3B staining intensity compared to primary tumors (p < 0.0001). Similar results were obtained for breast carcinoma microarrays where 73% (447/611) of primary tumors showed high levels of autophagy and this correlated with poor patient outcome (p < 0.001). Thus autophagy appears to be a constitutive metabolic state for a majority of malignant melanomas and breast carcinomas. The diverse origins and functions of these cells suggests that autophagy may be prevalent in other malignancies as well. Thus therapies targeting autophagy should be considered as a means to deprive cancer cells of an important energy source. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5106.

Abstract 828: Progranulin is a good predictive biomarker in ovarian cancer patients followed in first remission

Abstract Both secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are upregulated and overexpressed in ovarian cancers (OvCa). SLPI has important function in carcinogenesis as a proliferation and survival factor. PGRN is a potent growth and survival factor for cancer cells, and binds to SLPI, the complex of which protects PGRN from degradation by elastase. Recently, human epididymis protein 4 (HE4), located at the same whey acidic protein (WAP) genomic locus as SLPI and with similar structure, has been FDA approved for monitoring OvCa recurrence. We explored the application of SLPI and PGRN as monitoring biomarkers for OvCa recurrence. Archived plasma samples from 23 OvCa patients in first clinical remission, that had been collected prospectively every 3 months until relapse, were used to measure SLPI and PGRN concentrations; archival CA125 results and HE4 measured using commercially available ELISA were controls. Initial PGRN concentration, at study entry, was identified as a predictive factor. Thirteen of 23 patients had elevated PGRN concentrations and normal CA125 at the time of clinical remission. Eleven of those 13 patients recurred within 18 months (p= <0.03), with sensitivity and specificity of 79% and 78%, respectively. HE4 progressively increased in 19 of 23 patients, and 9 patients had positive change >12 months prior to the clinical progression. Only one patient maintained stable HE4 concentration and remains in remission; 3 patients who had stable HE4 concentrations relapsed at 14, 18, and 30 months. Five patients are still in clinical remission, but HE4 concentrations are increased in 4 of 5. In our small panel, HE4 had sensitivity and specificity of 77% and 10%, respectively. For the first time, our work evaluated SLPI and PGRN as predictive and monitoring biomarkers for OvCa recurrence. Additional study is needed to validate the usefulness of PGRN as a predictive factor in OvCa remission. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 828.

Lens Epithelium-Derived Growth Factor (LEDGF/p75) is a cancer cell survival factor that controls the expression of decoy TRAIL-receptor 2 (DcR2)

Lens Epithelium-Derived Growth Factor (LEDGF/p75) is a cancer cell survival factor that controls the expression of decoy TRAIL-receptor 2 (DcR2)

Lens Epithelium-Derived Growth Factor (LEDGF/p75) is a cancer cell survival factor that controls the expression of decoy TRAIL-receptor 2 (DcR2)

Lens Epithelium-Derived Growth Factor (LEDGF/p75) is a cancer cell survival factor that controls the expression of decoy TRAIL-receptor 2 (DcR2)