Targeting GIPC/Synectin in Pancreatic Cancer Inhibits Tumor Growth

Muders, Michael H.; Vohra, Pawan K.; Dutta, Shamit K.; Wang, Enfeng; Ikeda, Yasuhiro; Wang, Ling; Udugamasooriya, D. Gomika; Memić, Adnan; Rupashinghe, Chamila N.; Baretton, Gustavo; Aust, Daniela E.; Langer, Silke; Datta, Kaustubh; Simons, Michael; Spaller, Mark R.; Mukhopadhyay, Debabrata

doi:10.1158/1078-0432.ccr-08-2837

Cited by 41 publications

(59 citation statements)

References 32 publications

(30 reference statements)

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“…The animal experiments were strictly carried out according to the guidelines of the IACUC. The human pancreatic cancer xenograft model 30-32 and orthotopic model 34 were established as described previously (REFS). The treatment of the mice with SP141 and vehicle controls, the tumor growth and clinical monitoring, and the evaluations of the tissue pathology are detailed in the Supplemental Methods.…”

Section: Methodsmentioning

confidence: 99%

“…20-34 We have also proposed and evaluated various anti-MDM2 strategies, including the use of antisense oligonucleotides targeting MDM2, 35-37 siRNA, 38 and natural and synthetic small molecule MDM2 inhibitors. 39-42 Although these molecules are effective in vitro and in vivo as MDM2 inhibitors and anticancer agents, 21,29 their clinical prospects may be limited for various reasons, such as the difficulties associated with delivering them to cancer cells, their dependence on wild type p53, side effects, and low bioavailability.…”

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confidence: 99%

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Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

et al. 2014

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BACKGROUND & AIMS: The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, such as many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS: We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1cells (injected into pancreata), in nude mice. RESULTS: We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 μM (0.38–0.50 μM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2–M phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75%, compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS: In a screen for specific inhibitors of MDM2, we identified a compound, called SP141, which reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

et al. 2014

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“…More recently, knockdown of GIPC1 led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model, and a cell-permeable GIPC-PDZ inhibitor significantly blocked tumor growth without toxicity. Interestingly, GIPC knockdown was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells, and IGF-IR is a drug target currently in clinical trials in ovarian cancer (Karp et al, 2009;Muders et al, 2009).…”

Section: Adrm1 Knockdown In Ovarian Cancermentioning

confidence: 99%

Knockdown of ovarian cancer amplification target ADRM1 leads to downregulation of GIPC1 and upregulation of RECK

Fejzo¹,

Ginther²,

Dering³

et al. 2011

Genes Chromosomes & Cancer

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Approximately 25,000 ovarian cancers are diagnosed in the United States annually, and 75% of cases are in the advanced stage when they are largely incurable. There is a critical need for improved early detection tools and development of novel treatments. Recently, we showed that among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification and was significantly upregulated with respect to stage, recurrence, and metastasis. In addition, overexpression of ADRM1 correlated significantly with shorter time to recurrence and overall survival. Herein, array-CGH and microarray expression of ovarian cancer cell lines provides evidence consistent with the primary tumor data that ADRM1 is a 20q13 amplification target. Knockdown of ADRM1 in amplified ovarian cell-line OAW42 results in downregulation of growth factor GIPC1 and upregulation of tumor-suppressor RECK RNA and protein. In our dataset of 141 ovarian primary tumors, ADRM1 overexpression significantly correlates with GIPC1 overexpression. In addition, there is a significant anticorrelation between ADRM1 overexpression and RECK expression. Further research is necessary to determine whether targeting knockdown of ADRM1 in 20q13-amplified ovarian cancers results in growth inhibition and tumor suppression via downstream targets GIPC1 and RECK.

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“…In pancreatic cancers, the PDZ protein GIPC1/synectin is often overexpressed (202). Importantly, blocking synectin's PDZ-binding potential in a mouse model of pancreatic tumor invasion results in the inhibition of tumor growth (203). Although the roles of the PDZ interactions of NHERF1, GIPC, and their cognate GPCRs have yet to be determined, it is easy to envisage that such GPCR/PDZ protein interactions are likely of importance in cancer growth and development.…”

Section: Endocrine Tumorsmentioning

confidence: 99%

Minireview: Role of Intracellular Scaffolding Proteins in the Regulation of Endocrine G Protein-Coupled Receptor Signaling

Walther

Ferguson

2015

Molecular Endocrinology

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The majority of hormones stimulates and mediates their signal transduction via G protein-coupled receptors (GPCRs). The signal is transmitted into the cell due to the association of the GPCRs with heterotrimeric G proteins, which in turn activates an extensive array of signaling pathways to regulate cell physiology. However, GPCRs also function as scaffolds for the recruitment of a variety of cytoplasmic protein-interacting proteins that bind to both the intracellular face and protein interaction motifs encoded by GPCRs. The structural scaffolding of these proteins allows GPCRs to recruit large functional complexes that serve to modulate both G protein-dependent and -independent cellular signaling pathways and modulate GPCR intracellular trafficking. This review focuses on GPCR interacting PSD95-disc large-zona occludens domain containing scaffolds in the regulation of endocrine receptor signaling as well as their potential role as therapeutic targets for the treatment of endocrinopathies.

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Targeting GIPC/Synectin in Pancreatic Cancer Inhibits Tumor Growth

Cited by 41 publications

References 32 publications

Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice

Knockdown of ovarian cancer amplification target ADRM1 leads to downregulation of GIPC1 and upregulation of RECK

Minireview: Role of Intracellular Scaffolding Proteins in the Regulation of Endocrine G Protein-Coupled Receptor Signaling

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