The cyclin‐dependent kinase inhibitor <scp>p27<sup>Kip1</sup></scp> interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

Elson, Daniel J.; Nguyen, Bach Mai Dolly; Wood, Rhand; Zhang, Yi; Puig-Sanvicens, Verónica; Kolluri, Siva Kumar

doi:10.1002/1873-3468.14434

Cited by 9 publications

(7 citation statements)

References 68 publications

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“…For p27 Kip1 , protein expression was increased by either HG or exogenous H 2 O 2 , but neither of them influenced the gene expression of p27 Kip1 . Elson et al ( 13 ) demonstrated that in most situations, the gene expression of p27 is consistent in the cell cycle, indicating that the alteration of p27 occurs at the protein level, corresponding to our results. In a study on diabetic nephropathy, Aitken et al ( 14 ) demonstrated that HG inhibits cell proliferation (cell growth) in a dose-dependent manner, which is associated with the increased expression of p27 Kip1 .…”

Section: Discussionsupporting

confidence: 90%

Role of reactive oxygen species in high concentration glucose-induced growth inhibition of human peritoneal mesothelial cells

Zhu¹,

Tang²,

Yuan³

et al. 2022

Ann Transl Med

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Background: To investigate the effects and mechanism of high concentration glucose (HG), exogenous hydrogen peroxide (H 2 O 2 ), and antioxidants on the cell growth (cell proliferation) of human peritoneal mesothelial cells (HPMCs).Methods: All tests were conducted on cultured HPMCs (HMrSV5) in vitro. Various concentrations of glucose (0.1%, 1.35%, and 3.86%), H 2 O 2 (0.5 and 0.1 mmol/L), and antioxidants (pyruvate and catalase) were used in cell culture. Moreover, in order to study the interaction between these factors, HG and H 2 O 2 , HG and antioxidants, HG, H 2 O 2 , and antioxidants, were used respectively. After 12-24 h, phase-contrast microscopy was used to examine the morphological changes of HPMCs. DNA synthesis was detected by 3 H-thymidine incorporation to measure cell proliferation, and flow cytometry was used to evaluate the proportion of cells in G 1 phase. Furthermore, semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) was utilized to determine the mRNA expression of p21 Waf1 and p27 Kip1 [cyclin-dependent kinase inhibitors (CKIs)], while immunocytochemistry (ICC) and Western blotting were employed to measure the protein expression of p21 Waf1 and p27 Kip1 .Results: HG or low-dose exogenous H 2 O 2 resulted in hypertrophy and senescence of HPMCs, resulting in similar morphological changes. Both HG and exogenous H 2 O 2 (0.5 mmol/L) inhibited the proliferation of HPMCs and led to G1 phase arrest of HPMCs. The proportion of cells in G 1 phase increased. Moreover, HG enhanced the toxic effects of exogenous H 2 O 2 . Both HG and exogenous H 2 O 2 increased the expression of p21 Waf1 and p27 Kip1 . The addition of an antioxidant in HG medium arrested cells in the G 1 phase and improved the inhibited cell proliferation.Conclusions: Both HG and exogenous H 2 O 2 treatments can induce growth inhibition of HPMCs by arresting cell cycle progression, which is partially due to the increased expression of p21 Waf1 and p27 Kip1 . Thus, the effects of HG might be associated with endogenous reactive oxygen species (ROS), and it might be beneficial to use antioxidants in peritoneal dialysis (PD).

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Section: Discussionsupporting

confidence: 90%

Role of reactive oxygen species in high concentration glucose-induced growth inhibition of human peritoneal mesothelial cells

Zhu¹,

Tang²,

Yuan³

et al. 2022

Ann Transl Med

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“…We previously reported p27 Kip1 as a target gene of the AhR in hepatoma cells [58]. Furthermore, recently we identified a new regulatory cross-talk between p27 Kip1 and the AhR [59]. CABLES1 is a newly identified CDK inhibitor that has been demonstrated to play important roles in cell cycle regulation and suppression of tumour growth [60][61][62][63].…”

Section: Discussionmentioning

confidence: 99%

11‐Cl‐BBQ, a select modulator of AhR‐regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27^Kip1

et al. 2022

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Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and functions as a tumour suppressor in different cancer models. In the present study, we report detailed characterization of 11-chloro-7Hbenzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ) as a select modulator of AhR-regulated transcription (SMAhRT) with anti-cancer actions. Treatment of lung cancer cells with 11-Cl-BBQ induced potent and sustained AhR-dependent anti-proliferative effects by promoting G1 phase cell cycle arrest. Investigation of 11-Cl-BBQ-induced transcription in H460 cells with or without the AhR expression by RNA-sequencing revealed activation of p53 signalling. In addition, 11-Cl-BBQ suppressed multiple pathways involved in DNA replication and increased expression of cyclindependent kinase inhibitors, including p27 Kip1 , in an AhR-dependent manner. CRISPR/Cas9 knockout of individual genes revealed the requirement for both p53 and p27 Kip1 for the AhR-mediated anti-proliferative effects. Our results identify 11-Cl-BBQ as a potential lung cancer therapeutic, highlight the feasibility of targeting AhR and provide important mechanistic insights into AhR-mediated-anticancer actions.

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“…This can be mediated by increased expression of the p27 Kip1 cyclin-dependent kinase inhibitor or via further interactions of the AhR with Rb protein [ 66 ]. The relationship between the AhR and cell cycle regulators can be bi-directional, as both Rb and p27 Kip1 have been shown to regulate the AhR-mediated transcription [ 67 , 68 ]. Here, we found that the AhR antagonist CH-223191 inhibited the proliferation of HT-29 and HCT116 cells (in a similar manner as AhR KO), which seems to provide further support to the hypothesis that the AhR plays a positive role in the control of colon cancer cell proliferation, perhaps in a similar manner as in the above discussed models of liver carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells

Karasová

Procházková

Tylichová

et al. 2022

Cancers

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The aryl hydrocarbon receptor (AhR) plays a wide range of physiological roles in cellular processes such as proliferation, migration or control of immune responses. Several studies have also indicated that AhR might contribute to the regulation of energy balance or cellular metabolism. We observed that the AhR is upregulated in tumor epithelial cells derived from colon cancer patients. Using wild-type and the corresponding AhR knockout (AhR KO) variants of human colon cancer cell lines HCT116 and HT-29, we analyzed possible role(s) of the AhR in cell proliferation and metabolism, with a focus on regulation of the synthesis of fatty acids (FAs). We observed a decreased proliferation rate in the AhR KO cells, which was accompanied with altered cell cycle progression, as well as a decreased ATP production. We also found reduced mRNA levels of key enzymes of the FA biosynthetic pathway in AhR KO colon cancer cells, in particular of stearoyl-CoA desaturase 1 (SCD1). The loss of AhR was also associated with reduced expression and/or activity of components of the PI3K/Akt pathway, which controls lipid metabolism, and other lipogenic transcriptional regulators, such as sterol regulatory element binding transcription factor 1 (SREBP1). Together, our data indicate that disruption of AhR activity in colon tumor cells may, likely in a cell-specific manner, limit their proliferation, which could be linked with a suppressive effect on their endogenous FA metabolism. More attention should be paid to potential mechanistic links between overexpressed AhR and colon tumor cell metabolism.

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The cyclin‐dependent kinase inhibitor p27^Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

Cited by 9 publications

References 68 publications

Role of reactive oxygen species in high concentration glucose-induced growth inhibition of human peritoneal mesothelial cells

Role of reactive oxygen species in high concentration glucose-induced growth inhibition of human peritoneal mesothelial cells

11‐Cl‐BBQ, a select modulator of AhR‐regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27^Kip1

Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells

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The cyclin‐dependent kinase inhibitor p27Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

Cited by 9 publications

References 68 publications

Role of reactive oxygen species in high concentration glucose-induced growth inhibition of human peritoneal mesothelial cells

Role of reactive oxygen species in high concentration glucose-induced growth inhibition of human peritoneal mesothelial cells

11‐Cl‐BBQ, a select modulator of AhR‐regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27Kip1

Inhibition of Aryl Hydrocarbon Receptor (AhR) Expression Disrupts Cell Proliferation and Alters Energy Metabolism and Fatty Acid Synthesis in Colon Cancer Cells

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The cyclin‐dependent kinase inhibitor p27^Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

11‐Cl‐BBQ, a select modulator of AhR‐regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27^Kip1