Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.

Kamyar Zahedi,John L Cleveland,Robert A Casero,Manoocher Soleimani,Christina Destefano-Shields,Mark A Hall,Sharon Barone,Roger D Smith,Joanne R Doherty,Tracy Murray-Stewart,Marybeth Brooks,Matthew Dunworth,Weimin Li

doi:10.1371/journal.pone.0184570

Abstract

Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.

Highlights

Cisplatin, a platinum based compound, is a commonly used and highly effective chemotherapeutic agent utilized for the treatment of a variety of solid tumors [1, 2]
Using genetically engineered mice lacking SSAT or spermine oxidase (SMOX) (SSAT-KO or SMOX-KO), and through neutralization of toxic products of polyamine degradation we tested the following: 1) whether or not SSAT and SMOX expression levels increase in response to cisplatin treatment; 2) is cisplatin-induced AKI in part mediated via enhanced activity of polyamine catabolic enzymes and through generation of toxic products of polyamine degradation (e.g. H2O2 and aminoaldehydes); and 3) does activation of polyamine catabolism induces Endoplasmic reticulum stress response (ERSR), a pathway that is critical to the mediation of cell injury, tissue damage and organ dysfunction
These results demonstrate the presence of elevated SSAT activity (P

Summary

Introduction

A platinum based compound, is a commonly used and highly effective chemotherapeutic agent utilized for the treatment of a variety of solid tumors [1, 2]. The principal mode of cisplatin anti-tumor activity is via the formation of DNA–protein and DNA–DNA adducts [3, 4]. The non-repairable cisplatin-induced DNA damage results in the inhibition of tumor cell division and induction of apoptosis. Cisplatin usage is limited due its ototoxic and nephrotoxic side effects. More than 25% of patients treated with cisplatin develop renal failure and have to discontinue treatment [1, 5]. The molecular mechanisms of cisplatin nephrotoxicity are not completely elucidated and it is most likely a process that depends on the activation of multiple pathways and mechanisms

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Conclusion