Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

Abstract

Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO 2 , and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

“…Metabolic plasticity is a critical property that gives cancer cells the edge for expanding, persisting after therapeutic hits and evading immune surveillance [195]. Recently, metabolic reprogramming has been associated with acquired sensitivity to ferroptosis, thus opening up new opportunities to treat therapy-insensitive tumors [1].…”

The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity

“…Tumor cells reorganize metabolic pathways to supply ATP, building blocks for macromolecule biosynthesis, and redox molecules required to cell proliferation, invasion, migration, and other processes essential for malignancy, including chemo resistance ( 49 ). Consequently, the current research focus on metabolic reprogramming on the development and progression of human cancers reflects these hallmarks of cancer ( 5 , 50 ).…”

Switching diseased cells from cytosolic aerobic glycolysis to mitochondrial oxidative phosphorylation: A metabolic rhythm regulated by melatonin?

“…Likewise, this may also occur in younger individuals who are exposed to sufficiently bright light-at-night where the melatonin rhythm is suppressed or disrupted. [17][18][19] The ability of melatonin to impact pathological cells that use aerobic glycolysis and convert them to a more healthy cellular phenotype that utilizes mitochondrial oxidative phosphorylation may be an essential mechanism of the disease-inhibiting actions of this indoleamine. If this observation is valid, many diseased cells may only function as a pathological phenotype during the day and may actually be a healthier cell at night, provided there is a nighttime rise in circulating melatonin.…”