Nobiletin affects circadian rhythms and oncogenic characteristics in a cell-dependent manner

Don, Sujeewa S. Lellupitiyage; Robertson, Kelly L.; Lin, Hui-Hsien; Labriola, Caroline; Harrington, Mary E.; Taylor, Steven S.; Farkas, Michelle E.

doi:10.1371/journal.pone.0236315

Cited by 21 publications

(20 citation statements)

References 81 publications

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“…Compared to the U2OS cells as a positive control, we observed no persistent circadian bioluminescence rhythm, regardless of DMSO or NOB treatment. This agrees with a previous study showing severely disruption of circadian oscillation in MDA-MB-231 cells [ 53 ]. The lack of sustained circadian rhythms in MDA-MB-231 cells suggest that the inhibitory effects of NOB may be more directly related to RORs (RORα and RORγ) [ 39 , 54 – 58 ], rather than the clock machinery.…”

Section: Resultssupporting

confidence: 94%

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

Kim

et al. 2022

Cell Death Dis

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Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB–ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.

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Section: Resultssupporting

confidence: 94%

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

Kim

et al. 2022

Cell Death Dis

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“…We observed reduction in rhythmicity and amplitude enhancement of the U2OS oscillations. As circadian rhythms are found to be increasingly disrupted with disease severity and oncogenic characteristics [32] and even subtle renormalization of disrupted rhythms can reduce oncogenic features [48], our data highlights another connection between circadian oscillations and cancer, which should be studied further.…”

Section: Discussionmentioning

confidence: 84%

Macrophage Circadian Rhythms are Differentially Affected Based on Stimuli

et al. 2021

Preprint

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Macrophages are white blood cells of the innate immune system that play disparate roles in homeostasis and immune responses. As a result, they have the capability to alter their phenotypes to pro-inflammatory (M1) or anti-inflammatory (M2) subtypes in response to their environment. 8-15% of the macrophage transcriptome has circadian oscillations, including genes closely related to their functioning. As circadian rhythms are also associated with cellular phenotypes, we hypothesized that the polarization of macrophages to opposing subtypes might differently affect their circadian rhythms. We tested this by tracking the circadian rhythms of the mouse model macrophage cell line, RAW 264.7, which was stably transfected with Bmal1:luc and Per2:luc reporters, representing a positive and a negative component of the core molecular clock. The strength of rhythmicity was assessed using three measures: the relative power of the circadian band in the power spectral density, the rhythmicity index computed as the height of the third peak of the correlogram, and the maximum value of the chi square periodorgram. The period and amplitudes of the de-trended, smoothed time-series were estimated both by fitting to a damped cosine curve and by identifying the peak and trough of each cycle. M1 polarization decreased amplitudes and rhythmicities of both Bmal1:luc and Per2:luc, but did not significantly affect periods, while M2 polarization increased periods and caused no substantial alterations to amplitudes or rhythmicity. As macrophage phenotypes are also altered in the presence of cancer cells, we then tested the circadian effects of conditioned media from two mouse breast cancer cell lines on macrophage circadian rhythms. Media from highly agressive 4T1 cells caused loss of rhythmicity, while media from less aggressive EMT6 cells yielded no changes. As macrophages are known to play roles in tumors, and oncogenic features are associated with circadian rhythms, we also tested whether conditioned media from macrophages can alter circadian rhythms of cancer cells. We found that conditioned media from RAW 264.7 cells resulted in lower circadian rhythmicities and periods, but higher circadian amplitudes in human osteosarcoma, U2OS-Per2:luc cells. Taken together, our study shows that different circadian characteristics exist based on macrophage phenotypes, and suggests further that there is an association between circadian rhythms and macrophage polarization state. Additionally, our data shows that macrophages treated with breast cancer-conditioned media have circadian phenotypes similar to those of the M1 subtype, and cancer cells treated with macrophage-conditioned media have circadian alterations, providing insight to another level of cross-talk between macrophages and cancer cells that merits further investigation.

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“…Indeed, RORγ agonist, Lyc-55716, is currently in Phase I clinical trials as monotherapy as well as in combination with pembrolizumab (anti PD-1) in patients with advanced solid tumors. Recently, a small molecule, nobiletin, has been shown to have anti-oncogenic effects through restoration of circadian rhythmicity in a cell-type-dependent manner [ 147 , 148 ].…”

Section: Resultsmentioning

confidence: 99%

Clock at the Core of Cancer Development

Patel

Kondratov

2021

Biology

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To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.

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Nobiletin affects circadian rhythms and oncogenic characteristics in a cell-dependent manner

Cited by 21 publications

References 81 publications

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer

Macrophage Circadian Rhythms are Differentially Affected Based on Stimuli

Clock at the Core of Cancer Development

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