Falguni Parikh

Data from Inducible Nitric Oxide Synthase Drives mTOR Pathway Activation and Proliferation of Human Melanoma by Reversible Nitrosylation of TSC2

Esther López-Rivera Padmini Jayaraman Falguni Parikh Michael A. Davies Sühendan Ekmekçioglu

<div>AbstractMelanoma is one of the cancers of fastest-rising incidence in the world. Inducible nitric oxide synthase (iNOS) is overexpressed in melanoma and other cancers, and previous data suggest that iNOS and nitric oxide (NO) drive survival and proliferation of human melanoma cells. However, specific mechanisms through which this occurs are poorly defined. One candidate is the PI3K–AKT–mTOR pathway, which plays a major role in proliferation, angiogenesis, and metastasis of melanoma and other cancers. We used the chick embryo chorioallantoic membrane (CAM) assay to test the hypothesis that melanoma growth is regulated by iNOS-dependent mTOR pathway activation. Both pharmacologic inhibition and siRNA-mediated gene silencing of iNOS suppressed melanoma proliferation and in vivo growth on the CAM in human melanoma models. This was associated with strong downregulation of mTOR pathway activation by Western blot analysis of p-mTOR, p70 ribosomal S6 kinase (p-P70S6K), p-S6RP, and p-4EBP1. iNOS expression and NO were associated with reversible nitrosylation of tuberous sclerosis complex (TSC) 2, and inhibited dimerization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Ras homolog enriched in brain (Rheb), a critical activator of mTOR signaling. Immunohistochemical analysis of tumor specimens from stage III melanoma patients showed a significant correlation between iNOS expression levels and expression of the mTOR pathway members. Exogenously supplied NO was also sufficient to reverse the mTOR pathway inhibition by the B-Raf inhibitor vemurafenib. In summary, covalent modification of TSC2 by iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and proliferation of human melanoma. This model is consistent with the known association of iNOS overexpression and poor prognosis in melanoma and other cancers. Cancer Res; 74(4); 1067–78. ©2014 AACR.</div>

S-Nitrosylation

Nitrosylation

10.1158/0008-5472.c.6505883.v1

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Table S3 from Human Papilloma Virus Specific Immunogenicity and Dysfunction of CD8+ T Cells in Head and Neck Cancer

Sri Krishna Peaches Ulrich Eric Wilson Falguni Parikh Pooja Narang

Gene signatures for ssGSEA used in this study.

Table (database)

10.1158/0008-5472.22419666.v1

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Alexis Carrel (1873-1944).

PubMed (2015)

J V Pai-Dhungat Falguni Parikh

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Data from iNOS Expression in CD4+ T Cells Limits Treg Induction by Repressing TGFβ1: Combined iNOS Inhibition and Treg Depletion Unmask Endogenous Antitumor Immunity

Padmini Jayaraman Matthew G. Alfarano Peter F. Svider Falguni Parikh Geming Lu

<div>AbstractPurpose: Expression of inducible nitric oxide synthase (iNOS) in different cellular compartments may have divergent effects on immune function. We used a syngeneic tumor model to functionally characterize the role of iNOS in regulation of CD4+FOXP3+ regulatory T cells (Treg), and optimize the beneficial effects of iNOS inhibition on antitumor immunity.Experimental Design: Wild-type (WT) or iNOS knockout mice bearing established MT-RET-1 melanoma were treated with the small-molecule iNOS inhibitor L-NIL and/or cyclophosphamide alone or in combination. The effect of iNOS inhibition or knockout on induction of Treg from mouse and human CD4+ T cells in ex vivo culture was determined in parallel in the presence or absence of TGFβ1-depleting antibodies, and TGFβ1 levels were assessed by ELISA.Results: Whereas intratumoral myeloid-derived suppressor cells (MDSC) were suppressed by iNOS inhibition or knockout, systemic and intratumoral FOXP3+ Treg levels increased in tumor-bearing mice. iNOS inhibition or knockout similarly enhanced induction of Treg from activated cultured mouse splenocytes or purified human or mouse CD4+ T cells in a TGFβ1-dependent manner. Although either iNOS inhibition or Treg depletion with low-dose cyclophosphamide alone had little effect on growth of established MT-RET1 melanoma, combination treatment potently inhibited MDSC and Treg, boosted tumor-infiltrating CD8+ T-cell levels, and arrested tumor growth in an immune-dependent fashion.Conclusions: iNOS expression in CD4+ T cells suppresses Treg induction by inhibiting TGFβ1 production. Our data suggest that iNOS expression has divergent effects on induction of myeloid and lymphoid-derived regulatory populations, and strongly support development of combinatorial treatment approaches that target these populations simultaneously. Clin Cancer Res; 20(24); 6439–51. ©2014 AACR.</div>

10.1158/1078-0432.c.6523938

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Heimlich Maneuver.

PubMed (2008)

J V Pai-Dhungat Falguni Parikh

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Data from iNOS Expression in CD4+ T Cells Limits Treg Induction by Repressing TGFβ1: Combined iNOS Inhibition and Treg Depletion Unmask Endogenous Antitumor Immunity

Padmini Jayaraman Matthew G. Alfarano Peter F. Svider Falguni Parikh Geming Lu

<div>AbstractPurpose: Expression of inducible nitric oxide synthase (iNOS) in different cellular compartments may have divergent effects on immune function. We used a syngeneic tumor model to functionally characterize the role of iNOS in regulation of CD4+FOXP3+ regulatory T cells (Treg), and optimize the beneficial effects of iNOS inhibition on antitumor immunity.Experimental Design: Wild-type (WT) or iNOS knockout mice bearing established MT-RET-1 melanoma were treated with the small-molecule iNOS inhibitor L-NIL and/or cyclophosphamide alone or in combination. The effect of iNOS inhibition or knockout on induction of Treg from mouse and human CD4+ T cells in ex vivo culture was determined in parallel in the presence or absence of TGFβ1-depleting antibodies, and TGFβ1 levels were assessed by ELISA.Results: Whereas intratumoral myeloid-derived suppressor cells (MDSC) were suppressed by iNOS inhibition or knockout, systemic and intratumoral FOXP3+ Treg levels increased in tumor-bearing mice. iNOS inhibition or knockout similarly enhanced induction of Treg from activated cultured mouse splenocytes or purified human or mouse CD4+ T cells in a TGFβ1-dependent manner. Although either iNOS inhibition or Treg depletion with low-dose cyclophosphamide alone had little effect on growth of established MT-RET1 melanoma, combination treatment potently inhibited MDSC and Treg, boosted tumor-infiltrating CD8+ T-cell levels, and arrested tumor growth in an immune-dependent fashion.Conclusions: iNOS expression in CD4+ T cells suppresses Treg induction by inhibiting TGFβ1 production. Our data suggest that iNOS expression has divergent effects on induction of myeloid and lymphoid-derived regulatory populations, and strongly support development of combinatorial treatment approaches that target these populations simultaneously. Clin Cancer Res; 20(24); 6439–51. ©2014 AACR.</div>

10.1158/1078-0432.c.6523938.v1

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Abstract 4262: NR2F1 and SOX9 mediate reprogramming of tumor cells into dormancy: Potential role in dormant bone marrow DTCs

Cancer Research (2012)

María Soledad Sosa Yeriel Estrada Falguni Parikh Almudena Bosch-Gutierrez Esther Ekpin

Abstract Single disseminated tumor cells (DTCs) found in secondary organs (i.e. bone marrow BM, lung, liver) appear to activate a quiescence program and undergo a dormancy phase triggered by specific tissue microenvironment signals. The timing of this asymptomatic clinical phase may rely on specific signals that convert a previous non-permissive/non-proliferative environment into a permissive one, fueling metastasis development. The mechanisms underlying dormancy and means to maintain this state remain unknown. Here we show that the orphan nuclear receptor NR2F1/COUP-TF1 is silenced in breast and HNSCC tumors, cancer cell lines and MMTV-Neu and -Myc mouse tumor models. Surprisingly, retinoid signaling, stress signaling and microenvironmental cues from target organs (i.e. bone marrow) can induce re-expression of NR2F1 and dormancy of HNSCC cells. Forced NR2F1 re-expression resulted in induction of tumor cell quiescence in vivo and this effect depended on the expression of the transcription factor SOX9 and p27 induction. In contrast, RNAi-mediated silencing of NR2F1 or SOX9 interrupted the quiescence of dormant tumor cells. Further, quiescence induction was associated with p27, p15, p16 and HES-1. Mechanistic analysis revealed that NR2F1 is primarily nuclear and that its expression is activated by MKK6-p38α stress signaling and is negatively regulated by DNA promoter methylation. Lastly, we showed that atRA treatment followed 5-Aza-C treatment reprograms tumorigenic cells into dormancy in an NR2F1-dependent fashion. Our data suggest that re-expression of NR2F1 may promote reprogramming of aggressive tumor cells into dormancy identifying a new target for maintenance therapies for residual disease. 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 4262. doi:1538-7445.AM2012-4262

Reprogramming

10.1158/1538-7445.am2012-4262

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Medical philately. James Young Simpson & painless labor.

PubMed (2013)

J V Pai-Dhungat Falguni Parikh

Philately

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Dynamics of Assam agitation