Integrin αV modulates the cellular pharmacology of copper and cisplatin by regulating expression of the influx transporter CTR1.

Xinjian Lin,Gerald Manorek,Stephen B Howell,Xiying Shang,Mariama Fofana

doi:10.18632/oncoscience.22

Abstract

The αV integrin is expressed in most cancer cells where it regulates a diverse array of cellular functions essential to the initiation, progression and metastasis of solid tumors. However, little is known about how αV integrin modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. In this study, we found that down-regulation of αV sensitized human M21 cells to cisplatin (cDDP) through up-regulation of the copper influx transporter CTR1. Cells selected for low αV integrin expression (M21L) were more sensitive to cDDP, accompanied by increase in CTR1 mRNA and CTR1 protein levels, more intracellular cDDP accumulation and cDDP DNA adduct formation. Basal copper (Cu) content, Cu uptake, and Cu cytotoxicity were also increased. Transfection of a luciferase reporter construct containing the hCTR1 promoter sequence revealed an increase of the hCTR1 transcription activity in M21L cells. The basis for the increased hCTR1 transcription was related to an increase in the steady-state level of Sp1, a transcription factor known to drive hCTR1 expression. These results indicate that the αV integrin modulates sensitivity of human cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1, and introduce the concept that αV expression is linked to Cu homeostasis.

Highlights

Integrins are cell-surface glycoprotein receptors composed of a set of non-covalently associated α and β subunits
We report here that loss of αV integrin renders cells hypersensitive to the cytotoxic effect of cDDP, which is mediated through the Sp1 transcription factor that transcriptionally up-regulates the expression of Cu influx transporter CTR1 leading to both enhanced cDDP uptake, adduct formation and cell kill and changes in the level of intracellular Cu
Growth and survival of tumor cells are rigorously controlled by cell adhesion status, the engagement of integrins and other extracellular matrix (ECM)-binding surface receptors

Summary

Introduction

Integrins are cell-surface glycoprotein receptors composed of a set of non-covalently associated α and β subunits. Drug resistance induced by integrin-mediated interaction of tumor cells with the interstitial or extracellular matrix (ECM) has been reported in a variety of hematological malignancies [3,4,5,6] and solid cancers [7,8,9], and has been identified as “cell adhesion-mediated drug resistance”. Β1-integrin mediates resistance of leukemia cells to the apoptotic effects of chemotherapeutic drugs through regulation of the expression of Bcl-2 family proteins [6, 10]. The αV subunit, which is expressed in most cancer cells and plays an essential role in the formation of both cell–matrix and cell–cell interactions [11, 12], influences multiple processes including proliferation, survival and apoptosis [13,14,15,16]

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Conclusion