Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer

Winczyk, Katarzyna; Pawlikowski, Marek; Karasek, M

doi:10.1034/j.1600-079x.2001.310213.x

Cited by 48 publications

(34 citation statements)

References 13 publications

(14 reference statements)

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“…According to our earlier observations, MLT may enhance apoptosis in murine Colon 38 cancer [18]. The study of Eck et al [33] showing that MLT given together with retinoic acid induced apoptosis in MCF-7 mammary cancer cells is compatible with our findings.…”

Section: Discussionsupporting

confidence: 82%

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Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Winczyk¹,

Pawlikowski²,

Guerrero³

et al. 2002

Tumor Biol

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Experimental evidence has shown that melatonin (MLT) may act through both membrane and nuclear receptors. Moreover, it was proposed that the nuclear MLT receptor is identical with nuclear orphan receptors called RZR/ROR. Our earlier results suggest that the antitumor action of MLT depends mainly on nuclear signaling. In the present study, we investigated whether CGP 55644 (an antagonist of the nuclear RZR/RORα receptor) changes the oncostatic effects of MLT on murine Colon 38 cancer. The experiment was performed on adult male B6D2F1 mice. MLT or CGP were given either alone or combined during 10 days, and cell proliferation, apoptosis and the proliferation/apoptosis (P/A) ratio were determined. Cell proliferation was assessed by incorporation of bromodeoxyuridine into tumor cell nuclei (labeling index – LI). The number of apoptotic cells using the TUNEL method was considered as an index of apoptosis. It was found that MLT inhibited cell proliferation. Addition of CGP to MLT diminished the antiproliferative effect of MLT. Moreover, MLT increased the apoptotic index, but CGP decreased apoptosis. In addition, CGP given together with MLT blocked its proapoptotic effect. Given alone, MLT strongly lowered the P/A ratio, and addition of CGP to MLT abolished the effect of MLT on the P/A ratio. Based on our data, we conclude that nuclear RZR/RORα receptors participate in the oncostatic action of MLT.

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Section: Discussionsupporting

confidence: 82%

“…Regardless of the above observations, the study conducted in our laboratory has shown that MLT enhanced apoptosis in murine Colon 38 cancer cells [17]. Moreover, our recent experiments showed that CGP 52608 exerts similar proapoptotic effects [18].…”

Section: Introductionmentioning

confidence: 97%

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Winczyk¹,

Pawlikowski²,

Guerrero³

et al. 2002

Tumor Biol

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“…Moreover, administration of luzindole, a high-affinity melatonin membrane receptor antagonist, has been shown to attenuate the ability of melatonin to enhance splenic lymphocyte proliferation [53] and suppress experimental autoimmune encephalomyelitis [54]. Antiproliferative effects of melatonin have also been shown in LNCaP human prostate and murine colonic cancer through its MT 1 and RZR/ROR receptors, respectively [55,56].…”

Section: Discussionmentioning

confidence: 96%

Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system

Carrillo-Vico

Garcı́a-Pergañeda²,

Naji

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

120

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The neurohormone melatonin plays a fundamental role in neuroimmunomodulation of several mammalian species, including mice. This effect is supported by the existence of specific melatonin-binding sites in murine immunocompetent organs. Moreover, using melatonin receptor analogues, several effects of the neurohormone on mice physiology through its membrane and nuclear receptors have been described. The expression of these receptors has never been studied, despite indirect evidence showing the presence of melatonin receptor in the murine immune system. At present, the MT1 and MT2 membrane receptors, and nuclear receptors belonging to the RZR/ROR family have been related to the immunomodulator effect of melatonin. Here, we show the presence of membrane and nuclear melatonin-binding sites in mouse thymus and spleen, using the specific melatonin membrane (S 20098) and nuclear (CGP 52608) receptor agonist. To confirm the presence of melatonin receptors, we analyzed the presence of membrane and nuclear receptor mRNA and protein by RT-PCR, Southern blot, and Western blot. Thus, we show that MT1 and RORalpha receptor mRNA and protein are expressed in both thymus and spleen, while MT2 receptor mRNA is only detected in the thymus. This expression of melatonin receptors strongly supports the idea of an immunomodulatory role of melatonin through its receptors.

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“…For example, studies in the colon 38 carcinoma cell line identified both the nuclear receptor RZR/ROR (ROR·) and the cell membrane receptor MT2, but not MT1, as being responsible for the oncostatic effect of melatonin (41,52,68,69). In contrast, the MT1 receptor was responsible for the enhancement of the tumor suppressing effect of melatonin in MCF-7 breast cancer cells (39,53) and in S-91 murine melanoma cells (45).…”

Section: Discussionmentioning

confidence: 99%

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

Fischer

Żmijewski²,

Zbytek³

et al. 2006

Int J Oncol

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Abstract.Melatonin has been shown to have oncostatic effects on malignant melanoma in vitro and in vivo. We studied the growth suppressive effects of melatonin over a wide range of concentrations in four melanoma cell lines (SBCE2, WM-98, WM-164 and SKMEL-188) representative for different growth stages and phenotype. Melanoma cells were incubated with melatonin 10 -12 -10 -3 M, and proliferation and clonogenicity was assessed at 12 h and 14 days, respectively. We also determined the expression of cytosolic quinone oxidoreductases NQO1, NQO2 (known as MT3 receptor) and nuclear receptor ROR· by RT-PCR. Melatonin at pharmacological concentrations (10 -3 -10 -7 M) suppressed proliferation in all melanoma cell lines. In SKMEL-188 cells cultured in serum-free media, melatonin at low concentrations (10 -12 -10 -10 M) also slightly attenuated the proliferation. The effects of pharmacological doses of melatonin were confirmed in the clonogenic assay. Expression of NQO1 was detected in all cell lines, whereas NQO2 and nuclear receptor ROR· including its isoform ROR·4 were present only in SBCE2, WM-164 and WM-98. Thus, melatonin differentially suppressed proliferation in melanoma cell lines of different behaviour. The intensity of the oncostatic response to melatonin could be related to the cell-line specific pattern of melatonin cellular receptors and cytosolic binding protein expression.

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Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer

Cited by 48 publications

References 13 publications

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system

Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines

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