Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle.

Everolimus inhibits mammalian target of rapamycin complex 1 (mTORC1) and is known to cause induction of autophagy and G1 cell cycle arrest. However, it remains unknown whether everolimus-induced autophagy plays a critical role in its regulation of the cell cycle. We, for the first time, suggested that everolimus could stimulate autophagy-mediated cyclin D1 degradation in breast cancer cells. Everolimus-induced cyclin D1 degradation through the autophagy pathway was investigated in MCF-10DCIS.COM and MCF-7 cell lines upon autophagy inhibitor treatment using Western blot assay. Everolimus-stimulated autophagy and decrease in cyclin D1 were also tested in explant human breast tissue. Inhibiting mTORC1 with everolimus rapidly increased cyclin D1 degradation, whereas 3-methyladenine, chloroquine, and bafilomycin A1, the classic autophagy inhibitors, could attenuate everolimus-induced cyclin D1 degradation. Similarly, knockdown of autophagy-related 7 (Atg-7) also repressed everolimus-triggered cyclin D1 degradation. In addition, everolimus-induced autophagy occurred earlier than everolimus-induced G1 arrest, and blockade of autophagy attenuated everolimus-induced G1 arrest. We also found that everolimus stimulated autophagy and decreased cyclin D1 levels in explant human breast tissue. These data support the conclusion that the autophagy induced by everolimus in human mammary epithelial cells appears to cause cyclin D1 degradation resulting in G1 cell cycle arrest. Our findings contribute to our knowledge of the interplay between autophagy and cell cycle regulation mediated by mTORC1 signaling and cyclin D1 regulation.

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α-Mangostin Induces Apoptosis and Inhibits Metastasis of Breast Cancer Cells via Regulating RXRα-AKT Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.739658 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiuzhi Zhu ◽

Jialin Li ◽

Huiting Ning ◽

Zhidong Yuan ◽

Yue Zhong ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cancer Cells ◽

Signaling Pathway ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Akt Signaling ◽

Akt Signaling Pathway

Mangostin, which has the function of anti-inflammatory, antioxidant, and anticancer, etc, is one of the main active ingredients of the hull of the mangosteen. The main objective of the study was to elucidate its anti-cancer function and possible mechanism. α-Mangostin was separated and structurally confirmed. MTT method was used to check the effect of mangostin on breast cancer cell proliferation. Then the effect of α-Mangostin on the transcriptional activity of RXRα was tested by dual-luciferase reporter gene assay. And Western blot (WB) was used to detect the expression of apoptosis-related proteins or cell cycle-associated proteins after treatment. Also, this study was to observe the effects of α-Mangostin on the invasion of breast cancer cell line MDA-MB-231. α-Mangostin regulates the downstream effectors of the PI3K/AKT signaling pathway by degrading RXRα/tRXRα. α-Mangostin can trigger PARP cleavage and induce apoptosis, which may be related to the induction of upregulated BAX expression and downregulation of BAD and cleaved caspase-3 expression in MDA-MB-231 cells through blockade of AKT signaling. The experiments verify that α-Mangostin have evident inhibition effects of invasion and metastasis of MDA-MB-231 cells. Cyclin D1 was involved in the anticancer effects of α-Mangostin on the cell cycle in MDA-MB-231 cells. α-Mangostin induces apoptosis, suppresses the migration and invasion of breast cancer cells through the PI3K/AKT signaling pathway by targeting RXRα, and cyclin D1 has involved in this process.

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Comment on “Everolimus induces G1 cell cycle arrest through autophagy-mediated protein degradation of cyclin D1 in breast cancer cells”

AJP Cell Physiology ◽

10.1152/ajpcell.00421.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. C448-C449 ◽

Cited By ~ 1

Author(s):

Luigi Pirtoli ◽

Giuseppe Belmonte ◽

Marzia Toscano ◽

Paolo Tini ◽

Clelia Miracco

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Protein Degradation ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest

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Cyclopentenone causes cell cycle arrest and represses cyclin D1 promoter activity in MCF-7 breast cancer cells

Oncogene ◽

10.1038/sj.onc.1205293 ◽

2002 ◽

Vol 21 (14) ◽

pp. 2212-2226 ◽

Cited By ~ 17

Author(s):

Chin-Hui Hsiang ◽

Daniel S Straus

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Promoter Activity ◽

Cycle Arrest ◽

Mcf 7

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Abstract P6-04-01: Rapalog everolimus induces G1 cell cycle arrest through autophagy-mediated protein degradation of cyclin D1 in breast cancer cells

10.1158/1538-7445.sabcs17-p6-04-01 ◽

2018 ◽

Author(s):

G Chen ◽

X-F Ding ◽

H Bouamar ◽

K Pressley ◽

J Yang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Protein Degradation ◽

Cyclin D1 ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest

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223 PROGRESSION OF BREAST CANCER WAS CAUSED BY TREATMENT WITH BENZOPHENONE-1 AND NONYL-PHENOL VIA ALTERATION OF CELL CYCLE AND METASTASIS-RELATED GENES IN A CELLULAR MODEL

Reproduction Fertility and Development ◽

10.1071/rdv27n1ab223 ◽

2015 ◽

Vol 27 (1) ◽

pp. 201

Author(s):

S.-J. In ◽

K.-A. Hwang ◽

S.-H. Kim ◽

K.-C. Choi

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cyclin D1 ◽

Cancer Cells ◽

Cancer Progression ◽

Cathepsin D ◽

Breast Cancer Cells ◽

Negative Control ◽

Signalling Pathway ◽

Mcf 7

Endocrine disrupting chemicals (EDC) are defined as environmental compounds that may result in adverse health problems such as cancer proliferaition and metastasis in humans. Benzophenone-1 (2,4-dihydroxybenzophenone, BP-1) and nonyl-phenol (NP) are known as typical EDCs. They are discharged from numerous industrial products including plastics, pesticides, drugs, detergents, and cosmetics. In this study, we examined the effect of BP-1 and NP on the growth of MCF-7 human breast cancer cells expressing oestrogen receptors (ER) in comparison with E2 to assess their risk in cancer progression. In cell viability assay, BP-1 (10–5, 10–6, and 10–7 M) and NP (10–6 and 10–7 M) were determined to induce the proliferation of MCF-7 cells as well as E2 (10–9 M) was compared to a negative control treated with DMSO (P < 0.05). Next, to confirm that BP-1 and NP increase growth and metastasis of MCF-7 cells, the alterations in transcriptional and translational levels of related markers, i.e. cyclin D1, p21, and cathepsin D, were examined by reverse-transcription (RT)-PCR and Western blot assay. Cyclin D1 is a factor responsible for G1/S cell cycle transition and p21 is a potent cyclin-dependent kinase (CDK) inhibitor that arrests cell cycle in G1 phase. Cathepsin D is one of the proteases that are responsible for cancer progression and metastasis. Treatment of MCF-7 breast cancer cells with BP-1 (10–5 M) or NP (10–6 M) resulted in up-regulation of cyclin D1 and cathepsin D and down-regulation of p21 at transcriptional and translational levels as well as E2 (10–9 M) compared to a negative control treated with DMSO (P < 0.05). In addition, E2, BP-1, or NP-induced alterations of these genes were reversed by the presence of ICI 182 780 (10–8 M), an ER antagonist, suggesting that the changes in these gene expressions may be regulated by ER-dependent signalling pathway. In conclusion, these results suggest that BP-1 and NP, like E2, may accelerate the growth of MCF-7 breast cancer cells by regulating cell-cycle-related genes through ER-mediated signalling pathway. Furthermore, these EDCs can adversely affect human health by promoting cancer metastasis through the amplification of cathepsin D via ER-dependent signalling pathway.

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8-Chloro-Adenosine Inhibits Proliferation of MDA-MB-231 and SK-BR-3 Breast Cancer Cells by Regulating ADAR1/p53 Signaling Pathway

Cell Transplantation ◽

10.1177/0963689720958656 ◽

2020 ◽

Vol 29 ◽

pp. 096368972095865

Author(s):

Hong-Yue Ding ◽

Wan-Yong Yang ◽

Li-Hong Zhang ◽

Li Li ◽

Feng Xie ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Growth ◽

Cyclin D1 ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cell Growth Inhibition ◽

Protein Levels

8-Chloro-adenosine (8-Cl-Ado) has been shown to exhibit its antitumor activity by inducing apoptosis in human lung cancer A549 and H1299 cells or autophagy in chronic lymphocytic leukemia, and MDA-MB-231 and MCF-7 breast cancer cells. Adenosine deaminases acting on RNA 1 (ADAR1) is tightly associated with cancer development and progression. The aim of this study was to investigate the role of ADAR1 in the proliferation of MDA-MB-231 and SK-BR-3 breast cancer cell lines after 8-Cl-Ado exposure and its possible mechanisms. After 8-Cl-Ado exposure, CCK-8 assay was performed to determine the cell proliferation; flow cytometry was used to analyze the cell cycle profiles and apoptosis; and the protein levels of ADAR1, p53, p21, and cyclin D1 were measured by western blotting. The results showed that the cell proliferation was greatly inhibited, G1 cell cycle was arrested, and apoptosis was induced after 8-Cl-Ado exposure. ADAR1 and cyclin D1 protein levels were dramatically decreased, while p53 and p21 levels were increased after 8-Cl-Ado exposure. Moreover, the cell growth inhibition was rescued, apoptosis was reduced, and p53 and p21 protein levels were downregulated, while cyclin D1 was upregulated when cells were transfected with plasmids expressing ADAR1 proteins. More importantly, RNA-binding domain of ADAR1 is critical to the cell growth inhibition of breast cancer cells exposed to 8-Cl-Ado. Together, 8-Cl-Ado inhibits the cell proliferation, induces G1 phase arrest and apoptosis at least by targeting ADAR1/p53/p21 signaling pathway. The findings may provide us with insights into the role of ADAR1 in breast cancer progression and help us better understand the effects of 8-Cl-Ado in the treatment of breast cancer.

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