A study revealed that cancer cells that developed a high fermentative capacity became resistant and ceased responding to drug treatment, outlines Antonio Mazzocca.
The phenomenon of drug resistance poses a significant challenge in the field of cancer treatment. Our findings conducted at the University of Bari in Italy, and recently published in the American Journal of Physiology-Cell Physiology [1] indicate that as tumour cells develop drug resistance, they enhance their ability to ferment glucose into lactate at the expense of cellular respiration.
Known as the Warburg effect, this process was first described by the German biochemist Otto Warburg nearly a century ago.
Moreover, our team’s discovery reveals that cancer cells undergoing drug treatment exhibit mitochondrial alterations, increased lactate production, inhibited cellular respiration, and reduced efficiency in oxygen consumption.
Specifically, we found that cardiolipin, a crucial component of the mitochondrial membrane where cellular respiration occurs, is altered in the mitochondrion, the cell’s energy powerhouse. This alteration is important and linked to the blockage of cellular respiration by lactate, implying that the process is controlled by the extent of lactate fermentation.
Thus, lactate blocks oxidative phosphorylation (OxPhos), inhibiting cellular respiration and fuelling the Warburg effect. To our knowledge, this is the first description showing that lactate has a direct influence on OxPhos. This phenomenon determines the acquisition of ‘resilient’ behaviour in cancer cells, which enables them to withstand drug treatment.
Most importantly, the study reveals that simultaneously inhibiting lactate production and activating cellular respiration enables tumour cells to overcome drug resistance and become more sensitive to therapeutic agents. Specifically, we experimentally blocked lactate production by inhibiting lactate dehydrogenase and restored respiration using activators of complex IV in the mitochondrial respiratory chain. As a result, we observed that tumour cells became sensitive to drugs to which they had previously developed resistance.
The discovery that lactate fermentation, an ancient metabolic process, can control mitochondrial respiration can be contextualised within the framework of the systemic-evolutionary theory of the origin of cancer (SETOC), recently updated in the journal Molecular Medicine [2].
According to the SETOC, tumours, unlike normal tissues, exploit primordial processes preserved in our cells through evolution to resist hostile internal body environments. This can happen due to various conditions, including chronic inflammation, reduced oxygen supply to the cells, or a chronic excess of certain nutrients such as glucose.
In other words, cancer cells activate functions and programmes similar to those found in bacteria and yeasts, such as fermentation, to increase their resistance to environmental changes caused by chronic insults and to develop drug resistance.
The SETOC integrates an evolutionary biology principle – endosymbiosis – with systems biology. Endosymbiosis is the process by which the eukaryotic cell originated. About two and a half billion years ago, the union of two bacteria gave rise to an endosymbiont that would later become the eukaryotic cell. To be more precise, it is believed that an archaeobacterium, likely an Asgard archaeon, engulfed an α-proteobacterium, ultimately giving rise to the nucleus-cytoplasm of a proto-eukaryotic cell while the α-proteobacterium has evolved into the mitochondrion.
The systems biology approach used by SETOC focuses precisely on the complex interactions between these cellular systems: the nucleuscytoplasm (derived from the ancestral archaea) and the mitochondrion (derived from the ancestral proteobacteria).
To survive in changed conditions, the entire cell system readapts by becoming more robust, relying on ancient programmes conserved through evolution in our cell
Under physiological conditions, the two systems are perfectly integrated, ensuring the differentiation and cohesion of cells in tissues. In response to persistent insults that cause tissue remodelling, chronic inflammation, and fibrosis, cells adapt to the altered tissue microenvironment over time, leading to maladaptation.
De-endosymbiosis, or the progressive breakdown of the relationship between the nuclear-cytoplasmic and mitochondrial cellular subsystems, is the mechanism that drives maladaptation. This breakdown leads to uncoordinated cellular functions and behaviours, where one system, typically the old archaea, overpowers the other, ultimately resulting in neoplastic transformation.
To survive in changed conditions, the entire cell system readapts by becoming more robust, relying on ancient programmes conserved through evolution in our cells, such as lactic acid fermentation, ‘fumarate respiration’ or the reverse Krebs cycle, similar to those used by certain bacteria and yeasts.
The SETOC examines the evolutionary mechanisms of endosymbiosis that contribute to cancer development, moving beyond traditional Darwinian selection processes that solely attribute cellular competitive advantage to genetic mutations. De-endosymbiosis enables cancer cells to adapt, evolve, and thrive by activating ancient survival mechanisms preserved within our cells over the course of evolution.
Pharmacological therapies alone are not sufficient to prevent hostile conditions that quite often persist in our body when affected by cancer. Therefore, we need to expand the range of anticancer interventions, incorporating a multidisciplinary approach to achieve optimal results.
To achieve the best outcomes, it is important to combine lifestyle medicine interventions with standard therapies or follow-ups. This includes a very low-carbohydrate diet, regular physical activity tailored to age and condition, prioritising optimal sleep quality and stress management. These measures have consistently proven to be effective in significantly increasing the efficacy of medications and reducing recurrences.
Antonio Mazzocca is professor of General Pathology and Pathophysiology at the Interdisciplinary Department of Medicine, University of Bari School of Medicine
