Abstract
Acute administration of a high level of extracellular citrate displays an anti-proliferative effect on both in vitro and in vivo models. However, the long-term effect of citrate treatment has not been investigated yet. Here, we address this question in PC3 cells, a prostate-cancer-derived cell line. Acute administration of high levels of extracellular citrate impaired cell adhesion and inhibited the proliferation of PC3 cells, but surviving cells adapted to grow in the chronic presence of 20 mM citrate. Citrate-resistant PC3 cells are significantly less glycolytic than control cells. Moreover, they overexpress short-form, citrate-insensitive phosphofructokinase 1 (PFK1) together with full-length PFK1. In addition, they show traits of mesenchymal-epithelial transition: an increase in E-cadherin and a decrease in vimentin. In comparison with PC3 cells, citrate-resistant cells display morphological changes that involve both microtubule and microfilament organization. This was accompanied by changes in homeostasis and the organization of intracellular organelles. Thus, the mitochondrial network appears fragmented, the Golgi complex is scattered, and the lysosomal compartment is enlarged. Interestingly, citrate-resistant cells produce less total ROS but accumulate more mitochondrial ROS than control cells. Consistently, in citrate-resistant cells, the autophagic pathway is upregulated, possibly sustaining their survival. In conclusion, chronic administration of citrate might select resistant cells, which could jeopardize the benefits of citrate anticancer treatment.
Highlights
Alterations in metabolism are crucial for supporting aggressive proliferation, evasion from growth-inhibitory signals, cell migration, and metastatic cell dissemination [1].To survive in a hostile environment, to escape signal control, to migrate and to proliferate, cancer cells undergo “Warburg effect” by reducing oxidative phosphorylation (OXPHOS) and enhancing the rate of glycolysis and lactate production, even under aerobic conditions [2]
We investigated the effect of acute administration of citrate on the behavior of PC3 cells
We tested the acute effect of citrate administration on EPN cells, a line derived from normal epithelial human prostate spontaneously adapted to grow in culture, and on EPN-PKM cells, which derive from EPN cells transfected with a kinase-negative mutant of the non-receptor kinase Pyk2
Summary
Alterations in metabolism are crucial for supporting aggressive proliferation, evasion from growth-inhibitory signals, cell migration, and metastatic cell dissemination [1].To survive in a hostile environment, to escape signal control, to migrate and to proliferate, cancer cells undergo “Warburg effect” by reducing oxidative phosphorylation (OXPHOS) and enhancing the rate of glycolysis and lactate production (fermentation), even under aerobic conditions [2]. The main function of the prostate gland is to produce large amounts of citrate, secreted thereafter as a component of semen, supplying sperm with the source of energy necessary for their vitality and motility [6]. To this purpose, prostate epithelial cells in the peripheral zone accumulate zinc, which inhibits m-aconitase (ACO2) activity, preventing citrate oxidation. On the contrary, during early PCa cell transformation, activation of c-MYC fosters a metabolic switch from glycolytic to oxidative metabolism This allows tumor cells to become progressively more dependent on glutamine metabolism and increases lipid synthesis. Cancer relapse or recurrence represent major challenges in anti-cancer therapies and could be due to the pre-existence, induction, or selection of drug-resistant cells within the primary tumor
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