Abstract
Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.
Highlights
As indicated by Otto Warburg many years ago and accepted as a hallmark of cellular transformation, cancer cells entirely reprogram their metabolism to sustain hyperproliferation and growth in particular environmental conditions [1]
Different classes of mitocans exist and can be classified into eight groups, hexokinase inhibitors, Bcl-2 homology-3 (BH3) mimetics, thiol redox inhibitors, drugs targeting the voltage-dependent anionic channel (VDAC) or the adenine nucleotide translocator (ANT), agents interfering with the electron transport chain (ETC), lipophilic cations targeting the inner membrane, agents interfering with the mitochondrial DNA, and drugs acting on not well-defined sites [8]
Measurement of the basal cellular oxygen consumption rate (OCR) by Seahorse XF analyzer indicated a 40% increase of cellular respiration rate in cells grown in low glucose (Figure 1(c)), suggesting that MDA-MB-213 cells, in absence of glucose as main substrate for glycolysis, partially shifted from glycolysis to mitochondrial respiration
Summary
As indicated by Otto Warburg many years ago and accepted as a hallmark of cellular transformation, cancer cells entirely reprogram their metabolism to sustain hyperproliferation and growth in particular environmental conditions [1]. Oncogenes, and tumor suppressor mutations have an important role in this energetic shift to aerobic glycolysis [4, 5]. Another important feature of metabolic reprogramming of transformed cells is their reduced or strongly impaired mitochondrial function [3, 6]. There is a series of compounds targeting mitochondria, named mitocans, that are being tested as anticancer drugs. They usually lead to cancer cell death by inducing mitochondria destabilization with a consequent increase of reactive oxigen species (ROS) and activation of apoptotic signals [7, 8]. Among the compounds acting on the ETC, vitamin E analogues that in particular target Complex II have been
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