Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

Creamer, Bradley A.; Sloan, Shelly N. B.; Dennis, Jennifer; Rogers, Robert S.; Spencer, Sidney; McCuen, Andrew; Persaud, Purnadeo; Staudinger, Jeff

doi:10.3390/cells9102295

Cited by 14 publications

(8 citation statements)

References 80 publications

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“…It increased the BAX p53; caspase 3 and 9; while reducing the bcl-2. In addition, Creamer et al, (2020) literally found the pregnane X receptor (PXR, NR1I2) role in the breast tissue. The activation of PXR has the main function in apoptosis, and develops in acquired resistance to chemotherapeutic substances.…”

Section: Discussionmentioning

confidence: 99%

Pregnane Steroids from the Leaves of Melia Azedarach and Apoptotic Activity against T47D Cells

Ervina

Poerwono

Widyowati

et al. 2021

Asian Pac J Cancer Prev

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Objective: Nature has provided us with many pharmaceutical resources so far. Breast cancer shows an increasing trend in the world for the last decade and becomes one of five leading causes of death. Among the plants, Melia azedarach L. has been used widely in traditional medicine for many ailments including breast cancer. Following our previous findings that the ethyl acetate fraction was the most active cytotoxic fraction against T47D cells, we aimed to isolate the cytotoxic compounds and further elucidate their apoptotic mechanisms. Methods: The compounds were isolated through a series of chromatography with cytotoxicity evaluations. Identification of the isolated compounds was achieved by intensive spectroscopic analysis such as NMR, MS, and IR spectra. Cytotoxicity was evaluated by MTT method using doxorubicin as a reference compound. The expression of apoptosis-related factors was quantified by flow cytometry and immunocytochemistry. Results: Two isomers of pregnane steroids with molecular weight 330.2087 (C 21 H 30 O 3 ) were isolated from the EtOAc extract. Spectroscopic analysis revealed the structures as 17-ethylene-3,4-dihydroxy-14-methyl-18-norandrostene-16-one (1) and 17-ethylene-3,4-dihydroxy-5-pregnene-16-one (2), respectively. These compounds showed moderate cytotoxicity (IC 50 172.9 and 62.2 µg/mL, respectively) comparable to doxorubicin (IC 50 3.08 µg/ mL). The execution of apoptosis may be related to the increase of the ratio of BAX/bcl-2 of the cells. Conclusion: The EtOAc fraction of Melia azedarach L. leaves and the isolated 5-pregnene-16-one steroids are promising reagents for breast cancer treatment by introducing apoptosis to tumor cells. However, further researches are required to highlight its safety and usage in vivo.

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Section: Discussionmentioning

confidence: 99%

Pregnane Steroids from the Leaves of Melia Azedarach and Apoptotic Activity against T47D Cells

Ervina

Poerwono

Widyowati

et al. 2021

Asian Pac J Cancer Prev

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“…Nuclear receptors such as farnesoid X receptor (FXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPARα), liver X receptor (LXR), and androgen receptor, are candidates for the control of PXR expression. Additionally, possible coactivators that help the trafficking are steroid receptor coactivators (SRCs) 1, 2, and 3, peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), forkhead box O 1 transcription factor (FOXO1), protein arginine methyltransferase (PRMT), and p300 [61,62]. Furthermore, PXR may undergo epigenetic and post-translational modifications that affect its activity, so it may be selectively activated in some tumors [63].…”

Section: Discussionmentioning

confidence: 99%

High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma

et al. 2021

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Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells’ proliferative capacity, and overall disease-free patients’ survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells’ proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients’ survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients’ survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.

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“…While in mesenteric arteries, vasodilation was induced by the PXR agonist progesterone metabolite, probably via the induction of CYP enzymes. Furthermore, rifaximin which is a gut-specific human PXR ligand, is not effective for rodents; while pregnenolone-16 alpha carbonitrile (PCN) functions as a rodent-specific ligand (158)(159)(160)(161).…”

Section: Pregnane X Receptor (Pxr)mentioning

confidence: 99%

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

Alatshan

Benkő

2021

Front. Immunol.

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Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.

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Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

Cited by 14 publications

References 80 publications

Pregnane Steroids from the Leaves of Melia Azedarach and Apoptotic Activity against T47D Cells

Pregnane Steroids from the Leaves of Melia Azedarach and Apoptotic Activity against T47D Cells

High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

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