Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer

Karantanos, Theodoros; Tanimoto, Ryuta; Edamura, Kohei; Hirayama, Takahiro; Yang, Guang; Golstov, Alexei A.; Wang, Jianxiang; Kurosaka, Shinji; Park, Sanghee; Thompson, Timothy C.

doi:10.1002/ijc.28529

Cited by 11 publications

(10 citation statements)

References 27 publications

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“…VCaP cells were derived from a patient with mCRPC, while PC-3 cells are androgen receptor-negative metastatic PCa cells. We also included RWPE-1 cells, which are epithelial cells derived from the peripheral zone of an histologically normal adult human prostate and transfected with a single copy of human papillomavirus 18 [ 26 ]. The three cell lines were treated for 48 h with various concentrations of docetaxel (0.5, 1, 2, 5, 10, 20, 50, 75, and 100nM) and GLIPR1-ΔΤΜ (1, 2, 5, 10, 20, 40, 80,and 160 μg/ml) in different serum concentrations (0.1 % for PC-3 cells and 0.5 % for VCaP and RWPE-1 cells), and MTS assay was performed to evaluate the dose response and the IC50 for each single-agent treatment.…”

Section: Resultsmentioning

confidence: 99%

“…GLIPR1 was also found to be associated with destablizing phosphorylation of β-catenin and c-Myc, leading to their degradation [ 25 ]. Our group recently showed that GLIPR1-ΔTM is selectively taken up by PCa cells; activates apoptosis through ROS accumulation; and downregulates c-Myc [ 26 ]. Collectively, these results indicate that GLIPR1-ΔTM may be a good candidate for combination therapy with docetaxel, since it promotes PCa specific cell death through JNK activation, whereas it downregulates c-Myc signaling which has been extensively associated with the emergence of resistance to docetaxel through ERK1/2-c-Myc-CXCR4 signaling.…”

Section: Introductionmentioning

confidence: 99%

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GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells

et al. 2015

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BackgroundDocetaxel is the first chemotherapy agent approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminished its efficacy. JNK-mediated apoptosis is one of the mechanisms of docetaxel activity whereas ERK1/2-c-Myc-CXCR4 signaling is implicated in the development of resistance and induction of migration. The aim of this study was to evaluate the hypothesis that the combination treatment with docetaxel and GLIPR1-ΔTM will synergistically induce greater cell death and inhibit the emergence of resistance and development of metastatic potential in prostate cancer (PCa) cells.MethodsThe synergistic effects of the docetaxel and GLIPR1-ΔTM were evaluated with DNA fragmentation, DAPI staining and MTS using paired t-test and isobologram study. The effects of the drugs on JNK and ERK1/2-c-Myc-CXCR4 signaling were evaluated with Western blot, DNA fragmentation, and MTS assays using the JNK inhibitor SP600125, and CXCR4 siRNA. The results of docetaxel and GLIPR1-ΔTM combination on migration were examined with scratch assay using the CXCR4 inhibitor AMD3100 while our hypothesis was examined in vivo using VCaP orthotopic xenograft model.ResultsWe found that GLIPR1-ΔΤΜ synergized with docetaxel to induce apoptosis in VCaP and PC-3 PCa cells through induction of JNK signaling and concomitant inhibition of ERK1/2-c-Myc-CXCR4 signaling. We showed that JNK activation mediates the apoptotic effects of the drug combination and that CXCR4 knockdown increases its efficacy. We also found that the addition of GLIPR1-ΔΤΜ to docetaxel decreases the migration of VCaP and PC-3 cells. The combination treatment with docetaxel and GLIPR1-ΔTM inhibited tumor growth and decreased metastatic potential in VCaP xenografts more than single agents did.ConclusionsOur data suggested that addition of GLIPR1-ΔTM treatment in PCa cells increases the efficacy of docetaxel and may inhibit the emergence of drug resistance; potentially permitting a decrease of docetaxel dose for patients with mCRPC eliminating its systemic toxicities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0395-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells

et al. 2015

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“…It has been shown that the activity of CCNB2 , a key factor essential for transition from G2 to mitosis, is under the control of p53 which represses transcription of CCNB2 and causes arrest in G2 phase upon DNA damage [33]. Elevated expression of GLIPR1 , another p53 target, could further contribute to increased ROS production, promote cell cycle arrest and apoptosis, as observed in prostatic cancer cells [34]. On the other hand, pro-apoptotic BNIP3 was significantly downregulated by all treatments.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Toxic Responses of Organic Extracts from Diesel and Selected Alternative Fuels Engine Emissions in Human Lung BEAS-2B Cells

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Rössner

Vrbová

et al. 2016

IJMS

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This study used toxicogenomics to identify the complex biological response of human lung BEAS-2B cells treated with organic components of particulate matter in the exhaust of a diesel engine. First, we characterized particles from standard diesel (B0), biodiesel (methylesters of rapeseed oil) in its neat form (B100) and 30% by volume blend with diesel fuel (B30), and neat hydrotreated vegetable oil (NEXBTL100). The concentration of polycyclic aromatic hydrocarbons (PAHs) and their derivatives in organic extracts was the lowest for NEXBTL100 and higher for biodiesel. We further analyzed global gene expression changes in BEAS-2B cells following 4 h and 24 h treatment with extracts. The concentrations of 50 µg extract/mL induced a similar molecular response. The common processes induced after 4 h treatment included antioxidant defense, metabolism of xenobiotics and lipids, suppression of pro-apoptotic stimuli, or induction of plasminogen activating cascade; 24 h treatment affected fewer processes, particularly those involved in detoxification of xenobiotics, including PAHs. The majority of distinctively deregulated genes detected after both 4 h and 24 h treatment were induced by NEXBTL100; the deregulated genes included, e.g., those involved in antioxidant defense and cell cycle regulation and proliferation. B100 extract, with the highest PAH concentrations, additionally affected several cell cycle regulatory genes and p38 signaling.

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“…Cell viability was analyzed using an MTS CellTiter 96 AQueous One Solution cell proliferation assay (Promega, Madison, WI) as previously described [31]. A DNA fragmentation analysis was performed using a Cell Death Detection ELISA (Roche Applied Science, Indianapolis, IN) as previously described [32].…”

Section: Methodsmentioning

confidence: 99%

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

et al. 2016

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Caveolin-1 (Cav-1) is overexpressed in aggressive and metastatic prostate cancer (PCa) and induces PCa cell proliferation. Androgens mediate lipid synthesis through acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN). We investigated the Cav-1-mediated lipid synthesis in the development of castration resistance, and identified novel therapeutic opportunities. Using the PBCre+;Ptenloxp/loxp;PBCav-1+ mouse model we found that Cav-1 induction increased cancer incidence and growth, and ACC1-FASN expression in intact and castrated mice. We demonstrated that Cav-1 regulated ACC1 and FASN expression in an AR-independent way and increased palmitate synthesis using western blot analysis, qRT-PCR and mass spectrometry in vitro. By using FASN siRNA and C-75, we found that FASN inhibition was more effective in Cav-1-overexpressing cells. This inhibition was abrogated by ACC1si RNA, revealing the role of malonyl-CoA, an ACC1 product, as a mediator of cytotoxicity. Cav-1 was associated with ACC1 in human tumors and ACC1, FASN, and Cav-1 expression were increased in metastatic PCa compared to primary tumors and normal prostate epithelium. Palmitoleate and oleate levels were higher in BMA from patients with metastatic PCa who responded poorly to abiraterone acetate. Our findings suggest that Cav-1 promotes hormone resistance through the upregulation of ACC1-FASN and lipid synthesis under androgen deprivation, suggesting that FASN inhibition could be used to treat PCa that demonstrates Cav-1 overexpression.

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Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer

Cited by 11 publications

References 27 publications

GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells

GLIPR1-ΔTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells

Comparative Analysis of Toxic Responses of Organic Extracts from Diesel and Selected Alternative Fuels Engine Emissions in Human Lung BEAS-2B Cells

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

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