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Biol Open. 2019 Oct 15;8(10). pii: bio046961. doi: 10.1242/bio.046961.

Targeting of copper-trafficking chaperones causes gene-specific systemic pathology in Drosophila melanogaster: prospective expansion of mutational landscapes that regulate tumor resistance to cisplatin.

Author information

1
Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Athens 15701, Greece.
2
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens 11527, Greece.
3
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain.
4
Harvard Medical School, Massachusetts General Hospital Cancer Center (MGHCC), Charlestown, Massachusetts (MA) 021004, USA.
5
Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Athens 15701, Greece dstravop@biol.uoa.gr.

Abstract

Copper, a transition metal, is an essential component for normal growth and development. It acts as a critical co-factor of many enzymes that play key roles in diverse cellular processes. The present study attempts to investigate the regulatory functions decisively controlling copper trafficking during development and aging of the Drosophila model system. Hence, through engagement of the GAL4/UAS genetic platform and RNAi technology, we herein examined the in vivo significance of Atox1 and CCS genes, products of which pivotally govern cellular copper trafficking in fly tissue pathophysiology. Specifically, we analyzed the systemic effects of their targeted downregulation on the eye, wing, neuronal cell populations and whole-body tissues of the fly. Our results reveal that, in contrast to the eye, suppression of their expression in the wing leads to a notable increase in the percentage of malformed organs observed. Furthermore, we show that Atox1 or CCS gene silencing in either neuronal or whole-body tissues can critically affect the viability and climbing capacity of transgenic flies, while their double-genetic targeting suggests a rather synergistic mode of action of the cognate protein products. Interestingly, pharmacological intervention with the anti-cancer drug cisplatin indicates the major contribution of CCS copper chaperone to cisplatin's cellular trafficking, and presumably to tumor resistance often acquired during chemotherapy. Altogether, it seems that Atox1 and CCS proteins serve as tissue/organ-specific principal regulators of physiological Drosophila development and aging, while their tissue-dependent downregulation can provide important insights for Atox1 and CCS potential exploitation as predictive gene biomarkers of cancer-cell chemotherapy responses.

KEYWORDS:

Atox1; CCS; Chaperone; Cisplatin; Copper; Drosophila; Menkes; Wilson's

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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