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Cited by 57Arsenic contamination and mitigationCancer-related Molecular PathwaysProtein Kinase Regulation and GTPase Signaling

Akt Regulated Phosphorylation of GSK-3β/Cyclin D1, p21 and p27 Contributes to Cell Proliferation Through Cell Cycle Progression From G1 to S/G2M Phase in Low-Dose Arsenite Exposed HaCat Cells

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Chen, Yao, Liu, Xudan, Wang, Huanhuan, Liu, Shiyi, Hu, Nannan, Li, Xin·2019·Frontiers in Pharmacology
DOI 10.3389/fphar.2019.01176PMC PMC6798184
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Abstract

Arsenic is a toxic environmental contaminant. Long term exposure to arsenic through drinking water induces human cancers. However, it is as yet uncertain about the mechanisms of arsenic induced carcinogenesis. Although the effects of low-dose arsenicals on proliferation and cell cycle have been revealed by short time exposure, the evidences for long term exposure was seldom reported. The detailed mechanism has been unclear and supplemented constantly. In the present study, we used human keratinocytes (HaCat cells) to study the effects of long term, low-dose arsenite exposure on cell proliferation with emphasis on the Akt regulated cell cycle signaling pathways. We found that low-dose arsenite exposure could induce a dose dependent increase of cell proliferation and promotion of cell cycle progression from G1 to S/G2M phase, which could be attenuated by MK2206, a high selective inhibitor of Akt. Along with the dose dependent increase of phospho-AKT expression, the dose dependent increases of phospho-GSK-3β (Ser 9), phospho-p21 (Thr 145), phospho-p27 (Thr 157) and total cyclin D1 expression, and the dose dependent decreases of phospho-cyclin D1 (Thr 286) , p21 and p27 expression were also found in the arsenite exposed cells. Treatment with MK2206 could markedly reverse the expression of all of the above proteins. Our findings indicated that the phosphorylated activation of Akt played a role in the proliferation of HaCat cells upon long term, low-dose arsenite exposure through the phosphorylative regulation of its downstream cell cycle regulating factors of GSK-3β/cyclin D1, p21 and p27 which could induce the promotion of cell cycle progression from G1 to S/G2M phase.

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  • IGFBP7 interacts with the extracellular domain of IGF1R in the absence of IGF1/2, resulting in inhibition of the IRS1-PI3K-AKT signaling cascade and consequently maintaining normal activity of p21 and p27 within the nucleoplasm by avoiding their cytoplasmic retention mediated by AKT-triggered phosphorylation.

    “IGFBP7 interacts with the extracellular domain of IGF1R in the absence of IGF1/2, resulting in the inhibition of the IRS1-PI3K-AKT signaling cascade [20] and consequently maintaining the normal activity of p21 and p27 within the nucleoplasm by avoiding their cytoplasmic retention mediated by AKT-triggered phosphorylation [21].”

    From Ensemble of Time-Evolving SASP Gene Sets Identifies IGFBP7 and CDKN1A as a Potential Marker Pair for Senescent Fibroblast Subpopulations Across Tissues (2026) · cites this paper as [21]

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Cited by

Sorted by citations

Authors
Chen, Y., Liu, X., Wang, H., Liu, S., Hu, N., & Li, X.
Affiliations
China Medical University (CN)
Corresponding author
Li, Xin
ORCID
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2019-10-11
Volume
10
Pages
1176-1176
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2019.01176
PMC
PMC6798184
OpenAlex
W2980251308
Cited by
57
References
1
Citations by year
2026: 6 · 2025: 8 · 2024: 7 · 2023: 9 · 2022: 15 · 2021: 6 · 2020: 6
FWCI
2.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81872568)
  • Natural Science Foundation of Liaoning Province
Topics
  • Physical Sciences › Environmental Science › Environmental Chemistry › Arsenic contamination and mitigation
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
arsenite, low-dose arsenic exposure, arsenic carcinogenesis, HaCaT keratinocytes, cell proliferation, cell cycle progression, Akt signaling, GSK3β phosphorylation, cyclin D1, p21, p27, MK-2206, long-term exposure

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