1,25 dihydroxyvitamin D3 inhibits the proliferation of thyroid cancer stem-like cells via cell cycle arrest

The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], is a potent inhibitor of cellular proliferation as well as an inducer of differentiation of myeloid leukemic cells to macrophages. We have previously reported that a number of genes are upregulated by 1,25(OH)2D3 during myeloid differentiation, including the cyclin-dependent kinase (CDK) inhibitors p21, p27, 15, and p18, suggesting that cell cycle arrest and differentiation are tightly linked processes. We further explore here the relationship between growth inhibition and differentiation. We report that, upon 1,25(OH)2D3 treatment, U937 cells exhibited an early proliferative burst followed by growth inhibition and subsequent differentiation. Although CDK levels remain constant throughout, this transient increase in proliferation was accompanied by increases in cyclin A, D1, and E protein levels. p21 and p27 levels were also elevated during both the proliferative burst and subsequent inhibition of cell growth. Ectopic overexpression of p21 and/or p27 in U937 cells, in the absence of hormone, resulted in an induction of the expression of monocyte/macrophage-specific markers, whereas overexpression of p15 and p18 had no effect, suggesting that a subset of CDK inhibitors are important for both growth arrest and differentiation and that an early increase in proliferation is somehow a prerequisite for subsequent differentiation. However, no such biphasic behavior was detected in cells that are growth inhibited by 1,25(OH)2D3but do not differentiate, such as MCF-7 cells. Taken together, these results indicate that both growth stimulation and subsequent inhibition precede differentiation and involve induction of both cyclins and p21 and p27, whereas cell cycle arrest of differentiated cells can be achieved simply by elevations in CDK inhibitors.

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Induced Differentiation of U937 Cells by 1,25-dihydroxyvitamin D3 Involves Cell Cycle Arrest in G1 That Is Preceded by a Transient Proliferative Burst and an Increase in Cyclin Expression

Blood ◽

10.1182/blood.v93.8.2721 ◽

1999 ◽

Vol 93 (8) ◽

pp. 2721-2729 ◽

Cited By ~ 71

Author(s):

Nynke Y. Rots ◽

Antonio Iavarone ◽

Virginia Bromleigh ◽

Leonard P. Freedman

Keyword(s):

Cell Cycle ◽

Growth Inhibition ◽

Cell Cycle Arrest ◽

Cellular Proliferation ◽

Leukemic Cells ◽

Cdk Inhibitors ◽

U937 Cells ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Cycle Arrest

Abstract The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3[1,25(OH)2D3], is a potent inhibitor of cellular proliferation as well as an inducer of differentiation of myeloid leukemic cells to macrophages. We have previously reported that a number of genes are upregulated by 1,25(OH)2D3 during myeloid differentiation, including the cyclin-dependent kinase (CDK) inhibitors p21, p27, 15, and p18, suggesting that cell cycle arrest and differentiation are tightly linked processes. We further explore here the relationship between growth inhibition and differentiation. We report that, upon 1,25(OH)2D3 treatment, U937 cells exhibited an early proliferative burst followed by growth inhibition and subsequent differentiation. Although CDK levels remain constant throughout, this transient increase in proliferation was accompanied by increases in cyclin A, D1, and E protein levels. p21 and p27 levels were also elevated during both the proliferative burst and subsequent inhibition of cell growth. Ectopic overexpression of p21 and/or p27 in U937 cells, in the absence of hormone, resulted in an induction of the expression of monocyte/macrophage-specific markers, whereas overexpression of p15 and p18 had no effect, suggesting that a subset of CDK inhibitors are important for both growth arrest and differentiation and that an early increase in proliferation is somehow a prerequisite for subsequent differentiation. However, no such biphasic behavior was detected in cells that are growth inhibited by 1,25(OH)2D3but do not differentiate, such as MCF-7 cells. Taken together, these results indicate that both growth stimulation and subsequent inhibition precede differentiation and involve induction of both cyclins and p21 and p27, whereas cell cycle arrest of differentiated cells can be achieved simply by elevations in CDK inhibitors.

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Inhibition of Cot1/Tlp2 oncogene in AML cells reduces ERK5 activation and upregulates p27Kip1concomitant with enhancement of differentiation and cell cycle arrest induced by silibinin and 1,25-dihydroxyvitamin D3

Cell Cycle ◽

10.4161/cc.9.22.13790 ◽

2010 ◽

Vol 9 (22) ◽

pp. 4542-4551 ◽

Cited By ~ 39

Author(s):

Xuening Wang ◽

Elzbieta Gocek ◽

Victoria Novik ◽

Jonathan S. Harrison ◽

Michael Danilenko ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Cycle Arrest

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1,25-Dihydroxyvitamin D3 and cisplatin synergistically induce apoptosis and cell cycle arrest in gastric cancer cells

International Journal of Molecular Medicine ◽

10.3892/ijmm.2014.1664 ◽

2014 ◽

Vol 33 (5) ◽

pp. 1177-1184 ◽

Cited By ~ 17

Author(s):

ANYU BAO ◽

YAN LI ◽

YONGQING TONG ◽

HONGYUN ZHENG ◽

WEI WU ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Gastric Cancer Cells ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Cycle Arrest

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Arsenic trioxide‑induced cell apoptosis and cell cycle arrest are potentiated by 1,25‑dihydroxyvitamin D3 in human leukemia K562 cells

Oncology Letters ◽

10.3892/ol.2021.12770 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ya-Li Zhang ◽

Shu-Kai Qiao ◽

Xiao-Nan Guo ◽

Jin-Hai Ren ◽

Jing-Nan Zhang

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Arsenic Trioxide ◽

Cell Apoptosis ◽

K562 Cells ◽

Human Leukemia ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Cycle Arrest ◽

Human Leukemia K562 Cells

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Silencing of TCTN1 inhibits proliferation, induces cell cycle arrest and apoptosis in human thyroid cancer

Experimental and Therapeutic Medicine ◽

10.3892/etm.2017.4940 ◽

2017 ◽

Vol 14 (4) ◽

pp. 3720-3726 ◽

Cited By ~ 6

Author(s):

Peipei Xu ◽

Xiaotian Xia ◽

Zhili Yang ◽

Yuan Tian ◽

Jianzhong Di ◽

...

Keyword(s):

Cell Cycle ◽

Thyroid Cancer ◽

Cell Cycle Arrest ◽

Human Thyroid ◽

Cycle Arrest

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Selenite Induces Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species-Dependent Inhibition of the AKT/mTOR Pathway in Thyroid Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.668424 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhen Cheng ◽

Shuang Yu ◽

Weiman He ◽

Jie Li ◽

Tianyi Xu ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Cycle ◽

Thyroid Cancer ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Sodium Selenite ◽

Oxygen Species ◽

Cycle Arrest ◽

Intracellular Ros ◽

Thyroid Cancer Cells

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The in vitro findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.

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Lenvatinib Promotes the Antitumor Effects of Doxorubicin in Anaplastic Thyroid Cancer

10.21203/rs.3.rs-29005/v1 ◽

2020 ◽

Author(s):

Xi Su ◽

Jiaxin Liu ◽

Haihong Zhang ◽

Qingqing Gu ◽

Xinrui Zhou ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thyroid Cancer ◽

Combination Therapy ◽

Cell Cycle Arrest ◽

Anaplastic Thyroid Cancer ◽

Antitumor Efficacy ◽

Potential Candidate ◽

Antitumor Effects ◽

Cycle Arrest

Abstract Background Anaplastic thyroid cancer (ATC) is a kind of rare thyroid cancer with very poor prognosis. It is one of the deadliest cancers in human due to the aggressive behavior and resistance to treatment. Doxorubicin has been approved in ATC treatment as a single agent, but monotherapy still shows no improvement of the total survival in advanced ATC. Lenvatinib was investigated with encouraging results in treating the patients with radioiodine-refractory differentiated thyroid cancer (DTC). However, antitumor efficacy of combination therapy with lenvatinib and doxorubicin remains largely unclear. Methods The antitumor efficacy of combination therapy with lenvatinib and doxorubicin on ATC cell proliferation and was assessed by the MTT assay and colony formation. Flow cytometry were employed to assess ATC cells’ apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Result Lenvatinib monotherapy was less effective than doxorubicin in treating ATC cell lines and xenografts model. The combination therapy of lenvatinib and doxorubicin significantly inhibited ATC cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest in compared to lenvatinib or doxorubicin monotherapy. Conclusion Lenvatinib promotes the antitumor effects of doxorubicin in ATC cell and xenografts model. Lenvatinib/doxorubicin combination may be a potential candidate therapeutic approach for ATC.

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