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Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

ABSTRACT: Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

SUBMITTER: Wang J

PROVIDER: S-EPMC4725056 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

Wang Jing J Luo Cheng C Shan Changliang C You Qiancheng Q Lu Junyan J Elf Shannon S Zhou Yu Y Wen Yi Y Vinkenborg Jan L JL Fan Jun J Kang Heebum H Lin Ruiting R Han Dali D Xie Yuxin Y Karpus Jason J Chen Shijie S Ouyang Shisheng S Luan Chihao C Zhang Naixia N Ding Hong H Merkx Maarten M Liu Hong H Chen Jing J Jiang Hualiang H He Chuan C

Nature chemistry 20151109 12

Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as ...[more]

PMID: 26587712

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Project description:BackgroundAccumulated evidence supports the potent stimulating effects of multiple small molecules on the expansion of hematopoietic stem cells (HSCs) which are important for the therapy of various hematological disorders. Here, we report a novel, optimized formula, named the SC cocktail, which contains a combination of three such small molecules and four cytokines.MethodsSmall-molecule candidates were individually screened and then combined at their optimal concentration with the presence of cytokines to achieve maximum capacity for stimulating the human CD34+ cell expansion ex vivo. The extent of cell expansion and the immunophenotype of expanded cells were assessed through flow cytometry. The functional preservation of HSC stemness was confirmed by additional cell and molecular assays in vitro. Subsequently, the expanded cells were transplanted into sublethally irradiated NOD/SCID mice for the assessment of human cell viability and engraftment potential in vivo. Furthermore, the expression of several genes in the cell proliferation and differentiation pathways was analyzed through quantitative polymerase chain reaction (qPCR) during the process of CD34+ cell expansion.ResultsThe SC cocktail supported the retention of the immunophenotype of hematopoietic stem/progenitor cells remarkably well, by yielding purities of 86.6 ± 11.2% for CD34+ cells and 76.2 ± 10.5% for CD34+CD38- cells, respectively, for a 7-day culture. On day 7, the enhancement of expansion of CD34+ cells and CD34+CD38- cells reached a maxima of 28.0 ± 5.5-fold and 27.9 ± 4.3-fold, respectively. The SC cocktail-expanded CD34+ cells preserved the characteristics of HSCs by effectively inhibiting their differentiation in vitro and retained the multilineage differentiation potential in primary and secondary in vivo murine xenotransplantation trials. Further gene expression analysis suggested that the small-molecule combination strengthened the ability of the cytokines to enhance the Notch pathway for the preservation of HSC stemness, and inhibited the ability of the cytokines to activate the Wnt pathway for HSC differentiation.ConclusionsWe developed an optimal small-molecule/cytokine combination for the enhancement of HSC expansion via inhibition of differentiation. This approach indicates promising application for preparation of both the HSCs and the mature, functional hematopoietic cells for clinical transplantation.

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Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

Publications

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

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