Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Melanoma: HELP
Articles by Gregory S. Young
Based on 9 articles published since 2009
(Why 9 articles?)
||||

Between 2009 and 2019, Gregory Young wrote the following 9 articles about Melanoma.
 
+ Citations + Abstracts
1 Article The Exportin-1 Inhibitor Selinexor Exerts Superior Antitumor Activity when Combined with T-Cell Checkpoint Inhibitors. 2017

Farren, Matthew R / Hennessey, Rebecca C / Shakya, Reena / Elnaggar, Omar / Young, Gregory / Kendra, Kari / Landesman, Yosef / Elloul, Sivan / Crochiere, Marsha / Klebanov, Boris / Kashyap, Trinayan / Burd, Christin E / Lesinski, Gregory B. ·Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. · Department of Molecular Genetics, The Ohio State University, Columbus, Ohio. · Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio. · Target Validation Shared Resource, The Ohio State University, Columbus, Ohio. · Division of Internal Medicine, The Ohio State University, Columbus, Ohio. · Center for Biostatistics, The Ohio State University, Columbus, Ohio. · Karyopharm Therapeutics, Newton, Massachusetts. · Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. gregory.b.lesinski@emory.edu. ·Mol Cancer Ther · Pubmed #28148715.

ABSTRACT: Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth

2 Article Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells. 2014

Yang, Jennifer / Bill, Matthew A / Young, Gregory S / La Perle, Krista / Landesman, Yosef / Shacham, Sharon / Kauffman, Michael / Senapedis, William / Kashyap, Trinayan / Saint-Martin, Jean-Richard / Kendra, Kari / Lesinski, Gregory B. ·Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America. · Center for Biostatistics, The Ohio State University, Columbus, Ohio, United States of America. · Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, United States of America. · Karyopharm Therapeutics, Natick, Massachusetts, United States of America. ·PLoS One · Pubmed #25057921.

ABSTRACT: XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.

3 Article PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.). 2013

Nicholas, Courtney / Yang, Jennifer / Peters, Sara B / Bill, Matthew A / Baiocchi, Robert A / Yan, Fengting / Sïf, Saïd / Tae, Sookil / Gaudio, Eugenio / Wu, Xin / Grever, Michael R / Young, Gregory S / Lesinski, Gregory B. ·Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America. ·PLoS One · Pubmed #24098663.

ABSTRACT: Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.

4 Article Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines. 2012

Bill, Matthew A / Nicholas, Courtney / Mace, Thomas A / Etter, Jonathan P / Li, Chenglong / Schwartz, Eric B / Fuchs, James R / Young, Gregory S / Lin, Li / Lin, Jiayuh / He, Lei / Phelps, Mitch / Li, Pui-Kai / Lesinski, Gregory B. ·Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America. ·PLoS One · Pubmed #22899991.

ABSTRACT: The Janus kinase-2 (Jak2)-signal transducer and activator of transcription-3 (STAT3) pathway is critical for promoting an oncogenic and metastatic phenotype in several types of cancer including renal cell carcinoma (RCC) and melanoma. This study describes two small molecule inhibitors of the Jak2-STAT3 pathway, FLLL32 and its more soluble analog, FLLL62. These compounds are structurally distinct curcumin analogs that bind selectively to the SH2 domain of STAT3 to inhibit its phosphorylation and dimerization. We hypothesized that FLLL32 and FLLL62 would induce apoptosis in RCC and melanoma cells and display specificity for the Jak2-STAT3 pathway. FLLL32 and FLLL62 could inhibit STAT3 dimerization in vitro. These compounds reduced basal STAT3 phosphorylation (pSTAT3), and induced apoptosis in four separate human RCC cell lines and in human melanoma cell lines as determined by Annexin V/PI staining. Apoptosis was also confirmed by immunoblot analysis of caspase-3 processing and PARP cleavage. Pre-treatment of RCC and melanoma cell lines with FLLL32/62 did not inhibit IFN-γ-induced pSTAT1. In contrast to FLLL32, curcumin and FLLL62 reduced downstream STAT1-mediated gene expression of IRF1 as determined by Real Time PCR. FLLL32 and FLLL62 significantly reduced secretion of VEGF from RCC cell lines in a dose-dependent manner as determined by ELISA. Finally, each of these compounds inhibited in vitro generation of myeloid-derived suppressor cells. These data support further investigation of FLLL32 and FLLL62 as lead compounds for STAT3 inhibition in RCC and melanoma.

5 Article The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity. 2010

Bill, Matthew A / Fuchs, James R / Li, Chenglong / Yui, Jennifer / Bakan, Courtney / Benson, Don M / Schwartz, Eric B / Abdelhamid, Dalia / Lin, Jiayuh / Hoyt, Dale G / Fossey, Stacey L / Young, Gregory S / Carson, William E / Li, Pui-Kai / Lesinski, Gregory B. ·Department of Surgery, Arthur G, James Cancer Hospital and Richard J, Solove Research Institute, The Ohio State University, 410 W, 10th Ave, Columbus, OH 43210, USA. ·Mol Cancer · Pubmed #20576164.

ABSTRACT: BACKGROUND: We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. RESULTS: FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-gamma-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-gamma, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-gamma production when cultured with K562 targets as compared to vehicle (DMSO). CONCLUSIONS: These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy.

6 Article Modulation of SOCS protein expression influences the interferon responsiveness of human melanoma cells. 2010

Lesinski, Gregory B / Zimmerer, Jason M / Kreiner, Melanie / Trefry, John / Bill, Matthew A / Young, Gregory S / Becknell, Brian / Carson, William E. ·Department of Surgery Arthur G, James Cancer Hospital and Richard J, Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. ·BMC Cancer · Pubmed #20398276.

ABSTRACT: BACKGROUND: Endogenously produced interferons can regulate the growth of melanoma cells and are administered exogenously as therapeutic agents to patients with advanced cancer. We investigated the role of negative regulators of interferon signaling known as suppressors of cytokine signaling (SOCS) in mediating interferon-resistance in human melanoma cells. METHODS: Basal and interferon-alpha (IFN-alpha) or interferon-gamma (IFN-gamma)-induced expression of SOCS1 and SOCS3 proteins was evaluated by immunoblot analysis in a panel of n = 10 metastatic human melanoma cell lines, in human embryonic melanocytes (HEM), and radial or vertical growth phase melanoma cells. Over-expression of SOCS1 and SOCS3 proteins in melanoma cells was achieved using the PINCO retroviral vector, while siRNA were used to inhibit SOCS1 and SOCS3 expression. Tyr701-phosphorylated STAT1 (P-STAT1) was measured by intracellular flow cytometry and IFN-stimulated gene expression was measured by Real Time PCR. RESULTS: SOCS1 and SOCS3 proteins were expressed at basal levels in melanocytes and in all melanoma cell lines examined. Expression of the SOCS1 and SOCS3 proteins was also enhanced following stimulation of a subset of cell lines with IFN-alpha or IFN-gamma. Over-expression of SOCS proteins in melanoma cell lines led to significant inhibition of Tyr701-phosphorylated STAT1 (P-STAT1) and gene expression following stimulation with IFN-alpha (IFIT2, OAS-1, ISG-15) or IFN-gamma (IRF1). Conversely, siRNA inhibition of SOCS1 and SOCS3 expression in melanoma cells enhanced their responsiveness to interferon stimulation. CONCLUSIONS: These data demonstrate that SOCS proteins are expressed in human melanoma cell lines and their modulation can influence the responsiveness of melanoma cells to IFN-alpha and IFN-gamma.

7 Article Interleukin-29 binds to melanoma cells inducing Jak-STAT signal transduction and apoptosis. 2010

Guenterberg, Kristan D / Grignol, Valerie P / Raig, Ene T / Zimmerer, Jason M / Chan, Anthony N / Blaskovits, Farriss M / Young, Gregory S / Nuovo, Gerard J / Mundy, Bethany L / Lesinski, Gregory B / Carson, William E. ·Department of Surgery, Division of Surgical Oncology, The Ohio State University, Arthur G James Cancer Hospital and Richard J SoloveResearch Institute, Columbus, Ohio 43210, USA. ·Mol Cancer Ther · Pubmed #20103601.

ABSTRACT: Interleukin-29 (IL-29) is a member of the type III IFN family that has been shown to have antiviral activity and to inhibit cell growth. Melanoma cell lines were tested for expression of the IL-29 receptor (IL-29R) and their response to IL-29. Expression of IL-28R1 and IL-10R2, components of IL-29R, was evaluated using reverse transcription-PCR. A combination of immunoblot analysis and flow cytometry was used to evaluate IL-29-induced signal transduction. U133 Plus 2.0 Arrays and real-time PCR were used to evaluate gene expression. Apoptosis was measured using Annexin V/propridium iodide staining. In situ PCR for IL-29R was done on paraffin-embedded melanoma tumors. Both IL-28R1 and IL-10R2 were expressed on the A375, 1106 MEL, Hs294T, 18105 MEL, MEL 39, SK MEL 5, and F01 cell lines. Incubation of melanoma cell lines with IL-29 (10-1,000 ng/mL) led to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Microarray analysis and quantitative reverse transcription-PCR showed a marked increase in transcripts of IFN-regulated genes after treatment with IL-29. In the F01 cell line, bortezomib-induced and temozolomide-induced apoptosis was synergistically enhanced following the addition of IL-29. In situ PCR revealed that IL-10R2 and IL-28R1 were present in six of eight primary human melanoma tumors but not in benign nevi specimens. In conclusion, IL-29 receptors are expressed on the surface of human melanoma cell lines and patient samples, and treatment of these cell lines with IL-29 leads to signaling via the Jak-STAT pathway, the transcription of a unique set of genes, and apoptosis.

8 Article Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines. 2009

Bill, Matthew A / Bakan, Courtney / Benson, Don M / Fuchs, James / Young, Gregory / Lesinski, Gregory B. ·Department of Internal Medicine, Division of Hematology and Oncology, 302B Comprehensive Cancer Center, Columbus, OH 43210, USA. ·Mol Cancer Ther · Pubmed #19723881.

ABSTRACT: Curcumin has potential as a chemopreventative and chemotherapeutic agent, but its interactions with clinically relevant cytokines are poorly characterized. Because cytokine immunotherapy is a mainstay of treatment for malignant melanoma, we hypothesized that curcumin could modulate the cellular responsiveness to interferons and interleukins. As a single agent, curcumin induced a dose-dependent increase in apoptosis of human melanoma cell lines, which was most prominent at doses >10 micromol/L. Immunoblot analysis confirmed that curcumin induced apoptosis and revealed caspase-3 processing, poly ADP ribose polymerase cleavage, reduced Bcl-2, and decreased basal phosphorylated signal transducers and activators of transcription 3 (STAT3). Despite its proapoptotic effects, curcumin pretreatment of human melanoma cell lines inhibited the phosphorylation of STAT1 protein and downstream gene transcription following IFN-alpha and IFN-gamma as determined by immunoblot analysis and real time PCR, respectively. Pretreatment of peripheral blood mononuclear cells from healthy donors with curcumin also inhibited the ability of IFN-alpha, IFN-gamma, and interleukin-2 to phosphorylate STAT proteins critical for their antitumor activity (STAT1 and STAT5, respectively) and their respective downstream gene expression as measured by real time PCR. Finally, stimulation of natural killer (NK) cells with curcumin reduced the level of interleukin-12-induced IFN-gamma secretion, and production of granzyme b or IFN-gamma upon coculture with A375 melanoma cells or NK-sensitive K562 cells as targets. These data show that although curcumin can induce apoptosis of melanoma cells, it can also adversely affect the responsiveness of immune effector cells to clinically relevant cytokines that possess antitumor properties.

9 Article Bortezomib pre-treatment prolongs interferon-alpha-induced STAT1 phosphorylation in melanoma cells. 2009

Lesinski, Gregory B / Benninger, Kristen / Kreiner, Melanie / Quimper, Megan / Young, Gregory / Carson, William E. ·Division of Hematology and Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital, Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. gregory.lesinski@osumc.edu ·Cancer Immunol Immunother · Pubmed #19396596.

ABSTRACT: Bortezomib is a proteasome inhibitor that can synergize with interferon-alpha (IFN-alpha) to induce apoptosis in melanoma cells in vitro and inhibit tumor growth in vivo. We hypothesized that proteasome inhibition may be an effective means to sensitize melanoma cells to the direct effects of IFN-alpha. Pre-treatment of human melanoma cells with bortezomib led to significantly increased transcription of interferon-stimulated genes as determined by real-time PCR. Flow cytometric and immunoblot analyses indicated that the enhanced direct actions of IFN-alpha on melanoma cells were the result of prolonged phosphorylation of STAT1 (P-STAT1) on both the Tyrosine(701) and Serine(727) residues. In contrast, the enhanced IFN-alpha-induced P-STAT1 was not observed in peripheral blood mononuclear cells that were pre-treated with bortezomib. These data suggest that proteasome inhibition represents a mechanism to enhance the direct effects of IFN-alpha on melanoma cells thereby complementing its immunostimulatory properties.