Single amino acid arginine deprivation triggers prosurvival autophagic response in ovarian carcinoma SKOV3.

Galyna Shuvayeva,Federica Morani,Yaroslav Bobak,Ciro Isidoro,Oleh Stasyk,Rossella Titone,Natalia Igumentseva

doi:10.1155/2014/505041

Abstract

Autophagy is a process of cytosol-to-lysosome vesicle trafficking of cellular constituents for degradation and recycling of their building blocks. Autophagy becomes very important for cell viability under different stress conditions, in particular under amino acid limitation. In this report we demonstrate that single amino acid arginine deprivation triggers profound prosurvival autophagic response in cultured human ovarian cancer SKOV3 cells. In fact, a significant drop in viability of arginine-starved SKOV3 cells was observed when autophagy was inhibited by either coadministration of chloroquine or transcriptional silencing of the essential autophagy protein BECLIN 1. Enzymatic arginine deprivation is a novel anticancer therapy undergoing clinical trials. This therapy is considered nontoxic and selective, as it allows controlling the growth of malignant tumours deficient in arginine biosynthesis. We propose that arginine deprivation-based combinational treatments that include autophagy inhibitors (e.g., chloroquine) may produce a stronger anticancer effect as a second line therapy for a subset of chemoresistant ovarian cancers.

Highlights

It is established that some types of tumours are deficient in the biosynthesis of certain amino acids and often exhibit elevated sensitivity to deprivation of a corresponding single amino acid, both in vitro and, importantly, in vivo
In this report we demonstrate that single amino acid arginine deprivation triggers profound prosurvival autophagic response in cultured human ovarian cancer SKOV3 cells
No signs of PARP fragmentation as a reporter of apoptosis in arginine-starved SKOV3 cells were observed. This observation suggested that a substantial fraction of SKOV3 cells remained viable even after the prolonged arginine withdrawal indicating that these cells are rather resistant to this metabolic stress

Summary

Introduction

It is established that some types of tumours are deficient in the biosynthesis of certain amino acids and often exhibit elevated sensitivity to deprivation of a corresponding single amino acid (such as arginine, methionine, and asparagine), both in vitro and, importantly, in vivo (for recent reviews: [1,2,3,4,5]) This provided a rational basis for the development of metabolic anticancer therapies based on the application of recombinant amino acid degrading enzymes, such as asparaginase for the treatment of leukemias and other tumours [2, 5, 6]. We recently observed that tumour cells become profoundly more resistant to arginine withdrawal in in vitro 3D spheroid models relative to respective monolayer cultures [15, 16] This phenomenon is consistent with the results of animal studies and ongoing clinical trials which showed that arginine deprivation is effective in inhibiting tumour growth but not BioMed Research International in inducing tumour regression. The latter observation stimulates further search for more efficient rational combinational therapeutic approaches based on arginine deprivation

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Conclusion