Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs

Abstract

Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions. However, in response to elevated Cu, the Golgi exports ATP7A/B to post-Golgi sites where they promote sequestration and efflux of excess Cu to limit its potential toxicity. Growing tumors actively consume Cu and employ ATP7A/B to regulate the availability of this metal for oncogenic enzymes such as LOX and LOX-like proteins, which confer higher invasiveness to malignant cells. Furthermore, ATP7A/B activity and trafficking allow tumor cells to detoxify platinum (Pt)-based drugs (like cisplatin), which are used for the chemotherapy of different solid tumors. Despite these noted activities of ATP7A/B that favor oncogenic processes, the mechanisms that regulate the expression and trafficking of Cu ATPases in malignant cells are far from being completely understood. This review summarizes current data on the role of ATP7A/B in the regulation of Cu and Pt metabolism in malignant cells and outlines questions and challenges that should be addressed to understand how ATP7A and ATP7B trafficking mechanisms might be targeted to counteract tumor development.

Current Biomedical Use of Copper Chelation Therapy

“…In addition, gene expression analysis revealed multiple alterations in a variety of copper-binding or copper-sensitive proteins in colorectal [104] and breast cancers [105], suggesting that deregulation of copper homeostasis might contribute to cancer pathogenesis, development and metastasis. Collectively these indications provide support for copper chelation [106][107][108] and inhibition of copper -transporting ATPases [109] as potential strategies for cancer therapy.…”

Valproic Acid Synergizes With Cisplatin and Cetuximab in vitro and in vivo in Head and Neck Cancer by Targeting the Mechanisms of Resistance

“…This effect, is most likely due to a decrease of repair rate of DSB, depending on downmodulation of ERCC1, which has an essential role in the removal of DNA intra-strand crosslinks by nucleotide excision repair, thus resolving platinum-DNA damage ( Galluzzi et al, 2014 ), induced by VPA alone or in combined treatment. In parallel, the enhanced DNA damage obtained in combination setting is, most likely, also due to the increased concentrations of CDDP within the CDDP-resistant Cal27 cells, via VPA-induced upregulation of CDDP-influx channel CTR1 ( Galluzzi et al, 2014 ) and downregulation of the ATPase ATP7B involved in CDDP detoxification ( Galluzzi et al, 2014 ; Petruzzelli and Polishchuk, 2019 ). Notably, the increase of ERCC1 expression or of ATP7B and the loss of CTR1 have been all consistently reported as mechanisms of platinum resistance as well as predictors of poor response to platinum-based chemotherapy in cancer patients, including HNSCC ( Bisof et al, 2016 ; Sun et al, 2017 ; Petruzzelli and Polishchuk, 2019 ).…”

Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition

“…Undoubtedly, lysosomes play an important role in the heavy metal detoxification [ 88 ]. Interestingly, treatment of cancer cells with cisplatin resulted in the export of platinum via lysosomes and subsequently via exosomes [ 89 ]. The major factors involved in proteolytic degradation inside of lysosomes are proteins that belong to a class of cysteine proteases called cathepsins.…”