The Antiproliferative Response of Indole-3-Carbinol in Human Melanoma Cells Is Triggered by an Interaction with NEDD4-1 and Disruption of Wild-Type PTEN Degradation

Aronchik, Ida; Kundu, Aishwarya; Quirit, Jeanne G.; Firestone, Gary L.

doi:10.1158/1541-7786.mcr-14-0018

Cited by 61 publications

(55 citation statements)

References 49 publications

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“…Many natural compounds are also reported to inactivate the PI3K-AKT pathway either by activating PTEN or inactivating oncogenes that drive AKT activation. For example, the chemopreventive agent indole-3-carbinol (I3C), a natural indolecarbinol compound derived from the breakdown of glucobrassicin produced in cruciferous vegetables such as broccoli and Brussels sprouts, induced G1-phase cell-cycle arrest and apoptosis and inhibited the in vivo tumor growth rate by stabilization of PTEN in human melanoma cells that express wild-type PTEN, but not in cells with mutant or null PTEN genotypes [276]. Curcumin treatment significantly resulted in the inhibition of cell proliferation and an increase in the apoptosis rate through the upregulation of PTEN associated with a decrease in DNA methylation level via downregulation of DNMT3b in vivo and in vitro [277].…”

Section: Prophylactic and Therapeutic Potential Of Targeting Anti-mentioning

confidence: 99%

Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

Amin

Karpowicz

Carey

et al. 2015

Seminars in Cancer Biology

104

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The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.

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Section: Prophylactic and Therapeutic Potential Of Targeting Anti-mentioning

confidence: 99%

Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

Amin

Karpowicz

Carey

et al. 2015

Seminars in Cancer Biology

104

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show abstract

“…Another study found that I3C induces apoptosis in SK-MEL-5 melanoma cells by down-regulation of MITF [326]. Furthermore, I3C-mediated anti-proliferative effect was through interaction with neuronal precursor cell-expressed developmentally down regulated 4 and wild-type PTEN degradation in human melanoma cells [327]. I3C consumption was also associated with increased sensitivity to chemotherapy in a study of mice with B16 melanoma [328].…”

Section: Phytochemicals For the Prevention/treatment Of Melanomamentioning

confidence: 99%

Phytochemicals for the Management of Melanoma

Pal¹,

Hunt²,

Diamond³

et al. 2016

MRMC

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Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

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“…In clinical trials, I3C was tolerated well with minimal side effects (Reed et al, 2005). From a mechanistic viewpoint, we have established that the presence of specific I3C target proteins expressed in human cancer cells, such as Human Neutrophil Elastase (Nguyen et al, 2008, Aronchik et al, 2010, Aronchik et al, 2012) in breast cancer and the Neural precursor cell Expressed Developmentally Down-regulated 4 (NEDD4-1) a ubiquitin ligase whose function is critical in a subset of melanoma genotypes (Aronchik et al, 2014). We recently observed that I3C strongly inhibits oncogenic BRAF enzymatic activity with little effect on the wild type enzyme under conditions in this indolecarbinol disrupts proliferation of oncogenic BRAF-expressing melanoma cells (Kundu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Also, ectopic application of I3C directly inhibits skin tumor formation in mouse models (Srivastava and Shukla, 1998). We have observed that human melanoma cells with distinct mutational profiles are sensitive to the anti-proliferative effects of I3C (Aronchik et al, 2014), suggesting that this natural phytochemical could provide one component of a combinational therapy for human melanomas.…”

Section: Introductionmentioning

confidence: 99%

Cooperative antiproliferative signaling by aspirin and indole-3-carbinol targets microphthalmia-associated transcription factor gene expression and promoter activity in human melanoma cells

et al. 2016

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Anti-proliferative signaling of combinations of the nonsteroidal anti-inflammatory drug acetylsalicylic acid (aspirin) and indole-3-carbinol (I3C), a natural indolecarbinol compound derived from cruciferous vegetables, was investigated in human melanoma cells. Melanoma cell lines with distinct mutational profiles were sensitive to different extents to the anti-proliferative response of aspirin, with oncogenic BRAF-expressing G361 cells and wild type BRAF-expressing SK-MEL-30 cells being the most responsive. I3C triggered a strong proliferative arrest of G361 melanoma cells, and caused only a modest decrease in proliferation of SK-MEL-30 cells. In both cell lines, combinations of aspirin and I3C cooperatively arrested cell proliferation and induced a G1 cell cycle arrest, and nearly ablated protein and transcript levels of the melanocyte master regulator Micropthalmia Associated Transcription Factor isoform M (MITF-M). In melanoma cells transfected with a −333/+120 bp MITF-M promoter-luciferase reporter plasmid, treatment with aspirin and I3C cooperatively disrupted MITF-M promoter activity, which accounted for the loss of MITF-M gene products. Mutational analysis revealed that the aspirin required the LEF1 binding site, whereas, I3C required the BRN2 binding site to mediate their combined and individual effects on MITF-M promoter activity. Consistent with LEF1 being a down-steam effector of Wnt signaling, aspirin, but not I3C, down-regulated protein levels of the Wnt co-receptor LDL receptor-related protein-6 and β-catenin and up-regulated the β-catenin destruction complex component Axin. Taken together, our results demonstrate that aspirin-regulated Wnt signaling and I3C-targeted signaling pathways converge at distinct DNA elements in the MITF-M promoter to cooperatively disrupt MITF-M expression and melanoma cell proliferation.

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The Antiproliferative Response of Indole-3-Carbinol in Human Melanoma Cells Is Triggered by an Interaction with NEDD4-1 and Disruption of Wild-Type PTEN Degradation

Cited by 61 publications

References 49 publications

Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

Evasion of anti-growth signaling: A key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

Phytochemicals for the Management of Melanoma

Cooperative antiproliferative signaling by aspirin and indole-3-carbinol targets microphthalmia-associated transcription factor gene expression and promoter activity in human melanoma cells

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