The Aryl Hydrocarbon Receptor Contributes to the Proliferation of Human Medulloblastoma Cells

Dever, Daniel P.; Opanashuk, Lisa A.

doi:10.1124/mol.111.077305

Cited by 40 publications

(33 citation statements)

References 39 publications

(61 reference statements)

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“…It is clear that these studies demonstrate a potential clinical role for AhR antagonists in the treatment of glioblastoma. Other neurological cancers including medulloblastoma and pituitary adenomas also express an AhR that is pro-oncogenic (Dever and Opanashuk 2012; Jaffrain-Rea et al 2009), whereas the AhR enhances differentiation in neuroblastoma cells (Huang et al 2011) and TCDD induces apoptosis in PC12 cells (Sanchez-Martin et al 2010). These studies suggest different roles for the AhR and its ligand in brain cancers (Table 2).…”

Section: The Ahr and Its Ligand In Tumorigenesis And Cancer Chemotherapymentioning

confidence: 99%

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

2017

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The aryl hydrocarbon receptor (AhR) was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatics. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the AhR; however, during the last 25 years, it has become apparent that the AhR plays an essential role in maintaining cellular homeostasis. Moreover, the scope of ligands that bind the AhR includes endogenous compounds such as multiple tryptophan metabolites, other endogenous biochemicals, pharmaceuticals and health-promoting phytochemicals including flavonoids, indole-3-carbinol and its metabolites. It has also been shown that like other receptors, the AhR is a drug target for multiple diseases including cancer, where both AhR agonists and antagonists effectively block many of the critical hallmarks of cancer in multiple tumor types. This review describes the anti-cancer activities of AhR ligands and demonstrates that it is time to separate the AhR from TCDD and exploit the potential of the AhR as a novel target for cancer chemotherapy.

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Section: The Ahr and Its Ligand In Tumorigenesis And Cancer Chemotherapymentioning

confidence: 99%

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

2017

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“…[19][20][21] In contrast to an earlier study showing that dioxin exposure induces p27 KIP1 expression in murine thymus and hepatoma cells in an AHR-dependent manner, 40 recently published studies confirmed a higher basal expression of this protein in AHR-knockdown HaCaT KC 41 and AHRknockdown medulloblastoma cells. 42 Although a comparison between receptor activation and loss-of-function experiments has to be interpreted carefully, the observed repressive action of AHR on gene expression in the absence of any exogenous ligands may point to the potential presence of endogenous AHR ligands. 12 Noteworthy, a nuclear-localized constitutively active AHR that blocks gene expression, probably by inducing local epigenetic modifications, has also been previously described.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27 KIP1 and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer. With an annual incidence of two to three million new cases worldwide, non-melanoma skin cancer (NMSC) is one of the most frequent forms of cancer in humans (World Health Organization; http://www.who.int/uv/faq/skincancer/en/index1 .html). Typically, NMSCs, such as basal cell and squamous cell carcinomas, occur on sun-exposed areas of the skin, indicating that solar ultraviolet (UV) radiation, especially its UVB part (290-320 nm), is the most important etiological factor. 1,2 In fact, it is well established that UVB radiation gives rise to skin cancer without additional initiators or promoters and thus is a complete carcinogen. 1 Because of the thinning of the ozone layer, the increase in recreational sunbathing and the enhanced usage of UV tanning beds, the incidence of NMSC is expected to increase in future years, 1,2 underscoring the urgent need for novel preventives against UV-induced skin malignancies.When skin is exposed to solar radiation, high-energy UVB photons penetrate into the epidermis and initiate the so-called UVB response. 3 The main trigger of this stress response is the absorbance of UVB rays by DNA, which leads to the generation of highly mutagenic DNA photoproducts. 3,4 In addition, UVB exposure results in the formation...

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“…AHR activation by a ligand usually inhibits cell proliferation (Barhoover et al, 2010; Cheng et al, 2012; Elferink et al, 2001; Pang et al, 2008). The conclusion that AHR promotes cell proliferation is usually based on data obtained by ectopic overexpression of AHR (Wong et al, 2009) or knockdown of AHR by RNAi (Dever and Opanashuk, 2012; Kalmes et al, 2011; Yin et al, 2013). One interpretation of these data obtained from experiments not using ligand treatment is that AHR may have a ligand independent function which is important in the maintenance of cellular homeostasis.…”

Section: The Rb Connectionmentioning

confidence: 99%

Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma

Zhou

Zhang

Klibanski

2014

Molecular and Cellular Endocrinology

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Human pituitary adenomas are the most common intracranial neoplasms. Approximately 5% of them are familial adenomas. Patients with familial tumors carry germline mutations in predisposition genes, including AIP, MEN1 and PRKAR1A. These mutations are extremely rare in sporadic pituitary adenomas, which therefore are caused by different mechanisms. Multiple tumor suppressive genes linked to sporadic tumors have been identified. Their inactivation is caused by epigenetic mechanisms, mainly promoter hypermethylation, and can be placed into two groups based on their functional interaction with tumor suppressors RB or p53. The RB group includes CDKN2A, CDKN2B, CDKN2C, RB1, BMP4, CDH1, CDH13, GADD45B and GADD45G; AIP and MEN1 genes also belong to this group. The p53 group includes MEG3, MGMT, PLAGL1, RASSF1, RASSF3 and SOCS1. We propose that the tumor suppression function of these genes is mainly mediated by the RB and p53 pathways. We also discuss possible tumor suppression mechanisms for individual genes.

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The Aryl Hydrocarbon Receptor Contributes to the Proliferation of Human Medulloblastoma Cells

Cited by 40 publications

References 39 publications

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

Genetic and epigenetic mutations of tumor suppressive genes in sporadic pituitary adenoma

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