Transcriptional Regulation of Zinc Transporters in Human Osteogenic Sarcoma (Saos-2) Cells to Zinc Supplementation and Zinc Depletion

Alluri, Kiran; Nair, Krishna Pillay Madhavan; Kotturu, Sandeep Kumar; Ghosh, Sudip

doi:10.1007/s12011-019-01807-2

Cited by 9 publications

(17 citation statements)

References 31 publications

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“…Previous studies have suggested that ZIP10 may be an important channel for Zn uptake in OS cells, as its expression is upregulated when the environment is deficient in Zn [10]. In our study, we confirmed the importance of ZIP10 in managing the Zn content in OS.…”

Section: Discussionsupporting

confidence: 88%

“…In OS, however, the role of Zn transporters has not been well explored. A study involving the OS cell line Saos-2 showed that ZIP10 is upregulated under conditions of Zn deficiency [10], suggesting that ZIP10 may be an important transporter for OS cells to maintain intracellular Zn levels. As some evidence suggests chemoprotective properties for Zn in cancers, the relationship between ZIP10 and chemoresistance in OS cells warrants attention.…”

Section: Introductionmentioning

confidence: 99%

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ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

Shen

et al. 2021

J Exp Clin Cancer Res

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Background The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. Methods We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells. Results The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666–15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis. Conclusions We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

Shen

et al. 2021

J Exp Clin Cancer Res

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“…Regarding our results for the mRNA expression of zinc transporters and -binding proteins, we can confirm the previous findings [35,36] that zinc deficiency induces the expression of certain ZIPs, while the expression levels of MT1, MT2 and certain ZnTs are…”

Section: Discussionsupporting

confidence: 90%

“…Metallothioneins (MTs) are the most important zinc-binding proteins and are involved in the regulation of intracellular zinc homeostasis [38]. MTs were reported to be downregulated in zinc deficiency and upregu-lated in zinc supplementation [35,39], which we verified for A549 cells in regard to MT1 and MT2 mRNA expression (Figure 2d).…”

Section: Zinc Content In Media Affects Mrna Expression Of Zinc Transp...supporting

confidence: 64%

“…ZIPs lead to an intracellular zinc influx and normally show enhanced expression in zinc deficiency and decreased expression in zinc supplementation. ZnTs cause an efflux of zinc from the cytoplasm and are usually downregulated in cases of zinc deficiency and upregulated in zinc supplementation [34][35][36].…”

Section: Zinc Content In Media Affects Mrna Expression Of Zinc Transp...mentioning

confidence: 99%

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Zinc Status Impacts the Epidermal Growth Factor Receptor and Downstream Protein Expression in A549 Cells

Scheiermann

Puppa

Rink

et al. 2022

IJMS

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Zinc has been suggested to play a role in carcinogenesis and tumor progression. Serum zinc levels of lung cancer patients are for example lower than in healthy individuals. The activation and expression of the epidermal growth factor receptor (EGFR), which plays a role in tumor biology, are presumably influenced by zinc. EGFR activation influences cell adhesion and immune escape. This study provides insights into the impacts of zinc on the EGFR activation and expression of downstream proteins such as E-cadherin and PD-L1 in the alveolar carcinoma cell line A549. To model chronic changes in zinc homeostasis, A549 cells were cultured in media with different zinc contents. EGFR surface expression of unstimulated and stimulated A549 cells was determined by flow cytometry. EGFR phosphorylation as well as the protein expression of E-cadherin and PD-L1 were analyzed by Western blot. In our hands, chronic zinc deficiency led to increased EGFR surface expression, decreased E-cadherin protein expression and increased PD-L1 protein expression. Zinc supplementation decreased EGFR surface expression and PD-L1 protein expression. In summary, zinc-deficient A549 cells may display a more malignant phenotype. Thus, future clinical research should further focus on the possible benefits of restoring disturbed zinc homeostasis, especially in lung cancer patients.

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A Correlation Between Intracellular Zinc Content and Osteosarcoma

Meshkini

2020

Biol Trace Elem Res

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Transcriptional Regulation of Zinc Transporters in Human Osteogenic Sarcoma (Saos-2) Cells to Zinc Supplementation and Zinc Depletion

Cited by 9 publications

References 31 publications

ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

Zinc Status Impacts the Epidermal Growth Factor Receptor and Downstream Protein Expression in A549 Cells

A Correlation Between Intracellular Zinc Content and Osteosarcoma

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