Research Papers:

High salt induces P-glycoprotein mediated treatment resistance in breast cancer cells through store operated calcium influx

Duaa Babaer, Suneetha Amara, Michael Ivy, Yan Zhao, Philip E. Lammers, Jens M. Titze and Venkataswarup Tiriveedhi _

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Oncotarget. 2018; 9:25193-25205. https://doi.org/10.18632/oncotarget.25391

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Duaa Babaer1, Suneetha Amara2, Michael Ivy1, Yan Zhao3, Philip E. Lammers4, Jens M. Titze3,5 and Venkataswarup Tiriveedhi1,6

1Department of Biological Sciences, Tennessee State University, Nashville, TN, USA

2Department of Medicine, St Thomas-Midtown Hospital, Nashville, TN, USA

3Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

4Department of Medicine, Meharry Medical College, Nashville, TN, USA

5Cardiovascular and Metabolic Disorders program, Duke-NUS Medical School, Singapore

6Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

Correspondence to:

Venkataswarup Tiriveedhi, email: [email protected]

Keywords: breast cancer; salt; P-glycoprotein; store operated calcium entry; prostratin

Received: April 02, 2018     Accepted: April 28, 2018     Published: May 18, 2018


Recent evidence from our laboratory has demonstrated that high salt (Δ0.05 M NaCl) induced inflammatory response and cancer cell proliferation through salt inducible kinase-3 (SIK3) upregulation. As calcium influx is known to effect inflammatory response and drug resistance, we examined the impact of high salt on calcium influx in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 cells with high salt induced an enhanced intracellular calcium intensity, which was significantly decreased by store operated calcium entry (SOCE) inhibitor co-treatment. Further, high salt induced P-glycoprotein (P-gp) mediated paclitaxel drug resistance in breast cancer cells. Murine tumor studies demonstrated that injection of MCF-7 cells cultured in high salt, exerted higher tumorigenicity compared to the basal cultured counterpart. Knock down of SIK3 by specific shRNA inhibited tumorigenicty, expression of SOCE regulators and P-gp activity, suggesting SIK3 is an upstream mediator of SOCE induced calcium influx. Furthermore, small molecule inhibitor, prostratin, exerted anti-tumor effect in murine models through SIK3 inhibition. Taken together, we conclude that SIK3 is an upstream regulator of store operated calcium entry proteins, Orai1 and STIM1, and mediates high salt induced inflammatory cytokine responses and P-gp mediated drug resistance. Therefore, small molecule inhibitors, such as prostratin, could offer novel anti-cancer approaches.

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