Cell metabolism: idle for stuttering poison engines

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Cell metabolism: idle for stuttering poison engines
Cell metabolism: idle for stuttering poison engines

Idle for sputtering poison engines

Oxygen is Janus-faced: good for burning, but also toxic and dangerous because of the residues from use. All breathing body cells therefore always walk a fine line between too high and too low oxygen concentrations, between death by starvation and unhe althy excess. Tumor cells also prance between these abysses - and could soon receive a balance-disturbing nudge from new drugs. It happened a long time ago, suddenly and with serious consequences: a poison began to take over and soon threatened almost all life on earth. Oxygen, as the hostile substance is called, more and more entered the atmosphere above the germinating early life of our planet around 2.2 to 2.4 billion years ago. The culprits were cyanobacteria – the first and at that time the only organisms that mastered the photosynthesis that is common today and threatened all microbes living peacefully in the oxygen-free environment with the resulting waste product.

But no crisis without a chance: Only the increasing oxygen made life as we know it today possible - and at the same time condemned all conservative forms of life that insisted on the traditional anoxic lifestyle to vegetating in secret, closed to the air, shadowy existence. Adaptable and resourceful creatures, on the other hand, gradually used the fuel potential of the accumulating poison to their advantage: They learned to burn food components with oxygen in specially sourced cell power plants, the mitochondria, in a controlled manner and thereby gain much more energy than ever before.

Thus, for some, the threat finally became a necessity: Today, hardly any oxygen-breathing cell in our body can exist for a long time without O2 replenishment. Deficiency - the hypoxia - leads to cell death or at least to inconveniences: As was common in primeval times, the cell can only wrest energy from the molecules elicited from the food by glycolysis - the breakdown of sugar to pyruvate. Instead of being able to deliver the resulting intermediate product pyruvate to the mitochondria for respiration with oxygen, lactic acid, i.e. lactate, is cobbled together out of necessity. Energy gain: None - but the measure is necessary in order to be able to continue at least the previous utilization steps of glycolysis under conditions of oxygen deficiency.

This describes aspect one of the dilemma that cells find themselves in without an adequate oxygen supply: They can only produce a fraction of the energy as under aerobic conditions. The glycolysis, which supplies little energy, is massively boosted as a bridging measure - something that Louis Pasteur discovered more than a century ago and has since found its way into textbooks as the "Pasteur effect". The effect of over-acidification of the muscle cells due to lactate is known in overworked athletes' muscles. One consolation: The old adage that massive amounts of lactic acid are the cause of sore muscles has now been recognized as incorrect – and has therefore been removed from textbooks.

Aspect two of the hypoxia dilemma is more serious. With very small amounts of oxygen, the respiration machinery continues to run irregularly and even produces more reactive oxygen species, the so-called ROS. These radicals put the cell at great risk because of their aimless and rampant reactivity. Exactly those ROS are regarded as the most common cause of death of cells under hypoxia. A cell struggling for oxygen must therefore find ways and means to limit the formation of ROS.

The cellular way out of the dilemma is called HIF-1, which the work of two research groups led by Jung-Whan Kim from Johns Hopkins University and Ioanna Papandreou from Stanford University is now examining in more detail. HIF-1 is a transcription factor that has been known for some time. On the one hand, it acts on various genes in such a way that glycolysis is boosted (ensures more energy in the cell), but at the same time the enzyme that converts pyruvate for entry into the mitochondria is inhibited (restricts the unwanted production of ROS). In addition, HIF-1 accelerates its breakdown into lactate.

The teams led by Kim and Papandreou were now interested in all the intricacies of HIF-1 tasks in a very specific type of oxygen-depleted cell: young tumor cells. At the beginning of their fatal career, many tumors are finally ignored by the surrounding tissue and blood vessels and not exactly well supplied with oxygen. The cancer cells initially react like normal body cells under O2 poverty: They increase glycolysis with the help of HIF-1, the hypoxia master administrator. It has long been known that tumors with increased glycolytic activity grow faster and are more likely to have lethal consequences - now it is clear why.

If HIF-1 is switched off genetically under O2 deficiency, then tumor cells die off much faster, Kim and colleagues have now discovered in cell cultures [1]. In addition, the cells without HIF-1 become significantly more sensitive to cytotoxic anticancer drugs such as tirapazamine (TPZ), Papandreou and her team add. They also worked with tumors that lacked the HIF-1 regulators and were able to show that they die under oxygen deficiency even at very low levels of TP [2].

The only question that remains is how HIF-1 can be switched off selectively in tumor cells without affecting the useful mechanism against short-term oxygen deficiency in other cells in the body. Maybe this isn't necessary, Papandreou hopes - after all, HIF-1 is almost only switched on when there is a lack of oxygen. In the body of he althy people, this could perhaps be the case with overstrained athletes' muscles, sometimes also with heart muscle cells from acute infarction patients, or with a few other cell types in exceptional situations. However, early tumors always suffer from a lack of oxygen and are therefore particularly dependent on the program triggered by HIF-1. According to the new findings, Papandreaou, Kim and many others hope that a targeted cocktail of drugs such as TPZ and an HIF-1 inhibitor will promise future success in the eternal fight against cancer.

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