The cellular metallome serves as an important reservoir to meet the biological needs of the cell, serving as enzyme co-factors and ensuring proper protein folding. Recent studies have suggested that cancer cells adapt their metallome in order to accommodate rapid cellular growth and metabolism pathways. Thus, altering the cancer metallome may yield new avenues to target cancer and change the responsiveness to chemotherapy. Here, we aim to characterize and understand how changes in the ovarian cancer metallome affect sensitivity to the chemotherapy drug cisplatin. Five ovarian cancer cell lines were used in experiments: A2780, A2780/CP70, SKOV3, OVCAR3, and CAOV3. The metallome was manipulated by treating cells with either zinc, copper, magnesium, calcium, iron, manganese, or the metal chelator tetrathiomolybdate. Cisplatin sensitivity after metal treatment was measured by WST-1 cell proliferation assays. Metallomes were quantitated by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) by measuring the following metals: zinc, copper, magnesium, calcium, molybdenum, manganese, iron, phosphorous, and sulfur. Cellular metal concentrations were normalized to sulfur levels. Changes in cisplatin sensitivity were evaluated by measuring cellular cisplatin uptake by ICP-MS. Treatment of ovarian cancer cells with various metals resulted in differences in cellular proliferation and metallome composition. The changes in the metallome were not singular in nature because altering one metal resulted in changes in multiple metals. Cisplatin sensitivity was additionally affected under different metal treatments. Preliminary data suggest that cisplatin uptake was altered as a mechanism to mediate the cellular response to cisplatin, however other mechanisms such as DNA repair might also play a role. In conclusion, we demonstrate that perturbations of the cancer metallome result in changes of various metals, cellular proliferation, and sensitivity to the chemotherapy drug cisplatin. The data lend further insight into how an individual’s metallomic status, a combination of nutritional and harmful metal exposure, might result in the development and progression of cancer and affect the response to chemotherapy.
Citation Format: Lauren Amable, Eric Shide. Altering cisplatin sensitivity by manipulating the cellular metallome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4168. doi:10.1158/1538-7445.AM2017-4168