Zinc induces hephaestin expression via a PI3K-CDX2 dependent mechanism to regulate iron transport in intestinal Caco-2 cells

Hanuma Naik Ramavath; Purna Chandra Mashurabad; Puneeta Singh Yaduvanshi; Shobi Veleri; Paul A. Sharp; Raghu Pullakhandam

doi:10.1016/j.bbrc.2022.07.053

Zinc induces hephaestin expression via a PI3K-CDX2 dependent mechanism to regulate iron transport in intestinal Caco-2 cells

Hanuma Naik Ramavath, Purna Chandra Mashurabad, Puneeta Singh Yaduvanshi, Shobi Veleri, Paul A. Sharp, Raghu Pullakhandam^*

^*Corresponding author for this work

Nutritional Sciences

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Abstract

Zinc stimulates intestinal iron absorption via induction of divalent metal ion transporter (DMT1) and hephaestin (HEPH). While the increase in DMT1 is mediated via a PI3K/IPR2 axis, the mechanisms of Zn-induced HEPH expression downstream of PI3K remain elusive. In the current study we probed the role of Caudal-related homeobox transcription factor-2 (CDX2) on Zn-induced HEPH expression. Zn treatment of Caco-2 cells increased CDX2 phosphorylation and HEPH protein and mRNA expression. siRNA-silencing of CDX2 inhibited Zn-induced HEPH expression. LY294002, an antagonist of PI3K inhibited Zn-induced phosphorylation of CDX2, and downstream HEPH expression. These results suggest that increased expression of HEPH in intestinal cells following Zn treatment is mediated via a PI3K-CDX2 pathway.

Original language	English
Pages (from-to)	1-7
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	626
Early online date	10 Aug 2022
DOIs	https://doi.org/10.1016/j.bbrc.2022.07.053
Publication status	Published - 20 Oct 2022

Keywords

Caco-2 cells
CDX2
Hephaestin
Iron
Iron transporters
PI3K
siRNA
Zn

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Zinc induces hephaestin expression_RAMAVATH_Publishedonline10August2022_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 766 KBLicence: CC BY-NC-ND

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title = "Zinc induces hephaestin expression via a PI3K-CDX2 dependent mechanism to regulate iron transport in intestinal Caco-2 cells",

abstract = "Zinc stimulates intestinal iron absorption via induction of divalent metal ion transporter (DMT1) and hephaestin (HEPH). While the increase in DMT1 is mediated via a PI3K/IPR2 axis, the mechanisms of Zn-induced HEPH expression downstream of PI3K remain elusive. In the current study we probed the role of Caudal-related homeobox transcription factor-2 (CDX2) on Zn-induced HEPH expression. Zn treatment of Caco-2 cells increased CDX2 phosphorylation and HEPH protein and mRNA expression. siRNA-silencing of CDX2 inhibited Zn-induced HEPH expression. LY294002, an antagonist of PI3K inhibited Zn-induced phosphorylation of CDX2, and downstream HEPH expression. These results suggest that increased expression of HEPH in intestinal cells following Zn treatment is mediated via a PI3K-CDX2 pathway.",

keywords = "Caco-2 cells, CDX2, Hephaestin, Iron, Iron transporters, PI3K, siRNA, Zn",

author = "Ramavath, {Hanuma Naik} and {Chandra Mashurabad}, Purna and Yaduvanshi, {Puneeta Singh} and Shobi Veleri and Sharp, {Paul A.} and Raghu Pullakhandam",

note = "Funding Information: This study was supported in part by intramural grants from Indian Council of Medical Research-NIN (Project No. 12/BS03 ) and Department of Biotechnology grant [ BT/PR12128/PEN/20/960/2014 ]. HNR and PSY are supported by Fellowship from University grants Commission (UGC)- Govt of India . The funders had no role in study design or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

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AU - Ramavath, Hanuma Naik

AU - Chandra Mashurabad, Purna

AU - Yaduvanshi, Puneeta Singh

AU - Veleri, Shobi

AU - Sharp, Paul A.

AU - Pullakhandam, Raghu

N1 - Funding Information: This study was supported in part by intramural grants from Indian Council of Medical Research-NIN (Project No. 12/BS03 ) and Department of Biotechnology grant [ BT/PR12128/PEN/20/960/2014 ]. HNR and PSY are supported by Fellowship from University grants Commission (UGC)- Govt of India . The funders had no role in study design or preparation of the manuscript. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/10/20

Y1 - 2022/10/20

N2 - Zinc stimulates intestinal iron absorption via induction of divalent metal ion transporter (DMT1) and hephaestin (HEPH). While the increase in DMT1 is mediated via a PI3K/IPR2 axis, the mechanisms of Zn-induced HEPH expression downstream of PI3K remain elusive. In the current study we probed the role of Caudal-related homeobox transcription factor-2 (CDX2) on Zn-induced HEPH expression. Zn treatment of Caco-2 cells increased CDX2 phosphorylation and HEPH protein and mRNA expression. siRNA-silencing of CDX2 inhibited Zn-induced HEPH expression. LY294002, an antagonist of PI3K inhibited Zn-induced phosphorylation of CDX2, and downstream HEPH expression. These results suggest that increased expression of HEPH in intestinal cells following Zn treatment is mediated via a PI3K-CDX2 pathway.

AB - Zinc stimulates intestinal iron absorption via induction of divalent metal ion transporter (DMT1) and hephaestin (HEPH). While the increase in DMT1 is mediated via a PI3K/IPR2 axis, the mechanisms of Zn-induced HEPH expression downstream of PI3K remain elusive. In the current study we probed the role of Caudal-related homeobox transcription factor-2 (CDX2) on Zn-induced HEPH expression. Zn treatment of Caco-2 cells increased CDX2 phosphorylation and HEPH protein and mRNA expression. siRNA-silencing of CDX2 inhibited Zn-induced HEPH expression. LY294002, an antagonist of PI3K inhibited Zn-induced phosphorylation of CDX2, and downstream HEPH expression. These results suggest that increased expression of HEPH in intestinal cells following Zn treatment is mediated via a PI3K-CDX2 pathway.

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KW - Hephaestin

KW - Iron

KW - Iron transporters

KW - PI3K

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Zinc induces hephaestin expression via a PI3K-CDX2 dependent mechanism to regulate iron transport in intestinal Caco-2 cells

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