Copper is an important ion in the body that acts as a cofactor for many enzymes involved in cellular metabolism and respiration. It also plays fundamental roles in many signalling pathways as an allosteric regulator of multiple proteins.1 In considering the six hallmarks of cancer2, copper has been implicated in pathways and processes that contribute to the progression of cancer. The six hallmarks of cancer as written by Hanahan and Weinberg are: sustaining cell proliferation, evading growth suppressors, resisting cell death, inducing angiogenesis, activating invasion and metastasis and enabling replicative immortality.2 Copper’s role as a cofactor for cytochrome c oxidase directly impacts the ability of cancer cells to produce energy to sustain continuous cell proliferation; its role as a cofactor of the lysyl oxidase (LOX) proteins contributes to the ability of tumour cells to invade and metastasize to surrounding tissue.1 LOX proteins recruit myeloid cells to metastatic sites where they function to produce and recruit cytokines and growth factors necessary for cell proliferation.1 Copper also has the role of activating ULK 1 and 2 kinases which regulate the autophagy pathway in cells. This pathway is usually induced under stressful conditions within the cell and allows cancer cells to produce energy and synthesise the molecules they need to sustain the cell.1 In this manner, high copper levels allow cancer cells to resist cell death by self-sustenance through the autophagy process. Copper is an activator of proangiogenic factors including vascular endothelial growth factor (VEGF) which contribute to tumour growth and metastasis1 as this allows cancer cells to possess their own vascular network for transport of nutrients and metabolic wastes. Copper is an activator for the UBE2D group of proteins that add ubiquitin tags to proteins including growth suppressors, this results in the reduction of these growth suppressors that function to limit cell growth and proliferation.1 Copper helps cancer cells to evade growth suppressors and resist cell death with this role. When the various contributions that copper makes to tumour progression are considered, it is not surprising that cancer cells have been observed to have elevated copper levels1. Copper homeostasis is therefore a prime target as a method for treating cancer.
The therapeutics that are being considered for cancer that target copper homeostasis are copper chelators and ionophores. These compounds would have opposite functions in the treatment of cancer: chelators would function to make copper less available to the cell – disrupting the pathways previously mentioned that contribute to the progression of cancer, while ionophores would introduce toxic levels of copper into the cell that would initiate copper-dependent apoptosis, cuproptosis.1 The copper ionophore Disulfiram is an approved FDA drug to treat alcohol abuse and is in clinical trials for the treatment of Glioblastoma. It functions to generate reactive oxygen species (ROS) for cuproptosis as well as having other potent anticancer functions.1 Elesclomol is another copper ionophore with potential as a cancer therapeutic. It also generates ROS and increases the activity of an approved antitumor drug, Paclitaxel, all while not increasing the toxicity of the treatment.Elesclomol is in the clinical phase for treating melanoma.1 Tetrathiomolybdate (TM) is a copper chelator that was developed as a therapeutic against Wilson Disease and is being investigated as a therapeutic against breast cancer.1 The research and investigations so far into cuproplasia (copper-dependent cell growth and proliferation) and targeting copper homeostasis as a method to treat cancer have shown promising results. The current research available has shown that cancer cells have a strong response to copper-based therapeutics and the disruption of the balance maintained by copper homeostasis.
In the “Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis” article, Ramchandani et al. present and discuss the significant effect that the TM chelator has on mouse and human triple negative breast cancer (TNBC) cell lines as well as the discovery that activation of the 5’ AMP-activated protein kinase (AMPK) is important to reduce the metastatic properties of aggressive type cancers. TNBC is an aggressive type of cancer that has high potential for metastasis. The potential for these cancers to exhibit metastatic properties is in part due to the expression of stem cell transcription factors SOX2 and OCT4. Cells that express these proteins are capable of self-renewal and are resistant to chemotherapeutics.3 In this study, TM was observed to reduce metastasis in TNBC cells and in cells that express the SOX2 and OCT4 transcription factors. TM treatment was shown to specifically reduce mitochondrial ATP production and increased glycolysis.3 TNBC cell treatment with TM had a significant impact on cytochrome c oxidase activity, cytochrome c oxidase is involved in the final step of the electron transport chain for mitochondrial ATP production. A greater than 60% reduction in the oxidation of the enzyme was observed.3 A most interesting discovery was detailed in this study – TM treatment activates AMPK. AMPK signalling is known to play a role in cell migration and invasion.3 When human TNBC cells were treated with pharmacological activators of AMPK, the metastatic properties of the cells were reduced, fewer invading cells were observed.3 This is similar to the TM phenotype that was also observed. To investigate the role AMPK has on metastasis and invasion, AMPK was silenced in human TNBC cells, and they were treated with TM. The result was that the number of invading cells increased, which is a stark difference from how the cells reacted when treated with TM when AMPK was not inhibited. This result shows that inhibiting AMPK rescues the loss of invasion phenotype that resulted from TM treatment3 and is likely to spur investigations into AMPK activation as a cancer therapeutic. These investigations of copper and cancer are recent and the data that is being presented from these studies are promising. It should be interesting to observe in the upcoming years what more discoveries are made and the applications of these discoveries into cancer treatment.
References:
1. Ge, E. J.; Bush, A. I.; Casini, A.; Cobine, P. A.; Cross, J. R.; DeNicola, G. M.; Dou, Q. P.; Franz, K. J.; Gohil, V. M.; Gupta, S.; Kaler, S. G.; Lutsenko, S.; Mittal, V.; Petris, M. J.; Polishchuk, R.; Ralle, M.; Schilsky, M. L.; Tonks, N. K.; Vahdat, L. T.; Van Aelst, L.; Xi, D.; Yuan, P.; Brady, D. C.; Chang, C. J., Connecting copper and cancer: from transition metal signalling to metalloplasia. Nature Reviews Cancer 2022, 22 (2), 102-113.
2. Hanahan, D.; Weinberg, Robert A., Hallmarks of Cancer: The Next Generation. Cell 2011, 144 (5), 646-674.
3. Ramchandani, D.; Berisa, M.; Tavarez, D. A.; Li, Z.; Miele, M.; Bai, Y.; Lee, S. B.; Ban, Y.; Dephoure, N.; Hendrickson, R. C.; Cloonan, S. M.; Gao, D.; Cross, J. R.; Vahdat, L. T.; Mittal, V., Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. Nature Communications 2021, 12 (1), 7311.