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Int. J. Mol. Sci. 2018, 19(5), 1486; https://doi.org/10.3390/ijms19051486

Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis

1
Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
2
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
3
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
4
Center of Applied Nanomedicine, National Cheng Kung University, Tainan 70101, Taiwan
*
Author to whom correspondence should be addressed.
Received: 23 April 2018 / Revised: 10 May 2018 / Accepted: 12 May 2018 / Published: 16 May 2018
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Abstract

Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy. View Full-Text
Keywords: high-affinity copper transporter; hCtr1; Sp1; cisplatin; ovarian cancers; drug-resistance high-affinity copper transporter; hCtr1; Sp1; cisplatin; ovarian cancers; drug-resistance
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Lai, Y.-H.; Kuo, C.; Kuo, M.T.; Chen, H.H.W. Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis. Int. J. Mol. Sci. 2018, 19, 1486.

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