Hello everyone. Welcome back to my coursera class, Biochemical Principles of Energy Metabolism. This is session five during our week seven, right? So, week seven session five is about cancer, cancer cell metabolism. Cancer cell metabolism and bio-energetics. So, what is cancer? It's one of the devastating human diseases, right? As I know, cancer is the second leading cause of death in human society. And what's the definition of cancer? Why don't we just reveal about the concept of cancer biology? So, it's very simple, uncontrolled cellular division. Cancer cells, once normal cells, being cancerous and they undergo uncontrolled cellular proliferation and division. And further, they can infiltrate into neighboring tissues and destroy normal body function. So, there they can be metastatic. They can migrate from the original side of tumor formation into distant area of human body. Okay? All right, so I'm going to give you this slide again. So what is this slide? This is about glucose metabolism. Glycolysis, six carbon glucose split into three compounds like pyruvate. And then pyruvate getting into the mitochondria and through the Citric Acid Cycle and fully oxidized and those reducing powers obtained throughout those Krebs Cycle will be utilized to synthesize huge amount of ATP. This is flow of cellular respiration, glucose catabolic processes. So, what about cancer is quite unique? And you are looking at the famous legendary scientist Otto Warburg was a Nobel laureate. He discovered cancer cells specific metabolic process. So normal cells, as I just explained from the previous slide, completely oxidize glucose throughout the mitochondria system, that's the concept of cellular respiration, to maximize ATP extraction. However, Otto Warburg identified many types of cells, active tumor cells. They consume a lot of glucose huge amount of glucose. And then they secrete lactate from the cell rather than, so then is lactate fermentation, rather than full oxidization processes. This is very unique feature of cancer cell metabolism and this phenomenon is called Warburg effect. Named after Otto Warburg who discovered these cancer cells specific human metabolism. So, this is so-called aerobic glycolysis. Even the oxygen around, rather glycolysis is overall to just few ATP molecules produced but this glycolytic activity is humongously stimulated in tumor cells. Because of this enzyme, the pyruvate glycolysis product pyruvate will be fermented into lactate throughout this lactate dehydrogenase. And then that lactic acid will be secreted from the cells to the environment. So, mitochondria this is Krebs cycle dependent oxidative phosphorylation processes. The activity is quite lower, rather glycolysis activity and lactate fermentation activity is increased. This is Warburg effect in cancer cells. So why, these type of apparently quite toxical biological event happen in tumor cells? What is the metabolic benefits or biochemical benefits for these is quite weird metabolic adaptation in tumor cells? Okay, I'm showing again glycolysis is very high. And the glycolysis is supposed to be energy inefficient because only few ATP molecules can be produced. So again, this question is kind of a big question. It's a million dollar question. So, many oncologists and scientists trying to identify and trying to establish the exact reasons why tumor cells favor glycolysis, the Warburg effect. So, I summarized the four major possible answers based on the current understandings. So, tumor cells when they are rapidly accumulate and proliferate, the oxygen supply will be quite fluctuated. So, they want to have stable bio-energetic processes and they are more relying on glycolysis energetically. Once glycolytic rate is very high, overall ATP molecule synthesis will be okay to sustain tumor cell growth and proliferation. And secondly, tumors can metabolize glucose. So with the glycolysis and the other pass way, simple pass way pentose phosphate pathway they can generate NADPH. So, I need to introduce this pentose phosphate pathway. This is one of biochemical pathway out of the glucose degradation pathway in parallel to glycolysis through which finally NADPH is produced. I introduce the importance of NADPH as ensuring the cellular anti-oxidant environment. NADPH production throughout those glycolysis and pentose phosphate pathway can be used to protect tumor cells from oxidant stress. And secondly, NADPH is also very important core substrate for peracid synthesis. And those peracid and lipid synthesis will be used for active cell division. And many daughter cells after tumor cell division, they require many lipids. So, NADPH production will be secondary reason. And number three is cancer cells utilize many glycolic metabolic intermediate for other micro-molecule biosynthesis for example, glucose-6-phosphate from glycolysis will be used glycogen biosynthesis or ribose-5-phosphate synthesis. And ribose-5-phosphate obviously is building blocks for nucleic acid. So, many nucleic acid are needed to produce daughter cells because daughter cells require more genetic material. So, hydroxyacyl phosphate, one of the glycolytic metabolic pathway intermediates, will be used to triacylglyceride or lipid synthesis. And pyruvate from the glycolysis and can be used for amino acid biosynthesis. That's the reason number three. And reason number four is, cancer cells throughout the lactate fermentation, there's release lactic acid to the environment outside the cell. And when lactic acid accumulate around the tumor cells and those tumor microenvironment will be very acidic. And those acidic conditions will favor tumor invasion and suppress the immune cells which can kill tumor cells. So, those four reasons are current up to date like on summary for why tumor cells favor Warburg effect. So, these high glycolytic rate and glucose uptake specifically in tumor cells, can be used for diagnosing tumor tissues. And you're looking at the Fludeoxyglucose, this a radio of fluoride labeled glucose molecules, and by using the scanning analysis, we can monitor and track down the exact localization of highly glycolytic tumor cells. Because tumor cells are relying on glucose is quite addicted by glucose nutrients so glucose uptake, this Fludeoxyglucose uptake, rate is very high. And we can just monitor which regions are affected by tumor cells. So, for the therapeutics, many companies and oncologists and pharmacologists are trying to utilize this information, Warburg effect information, and trying to shut down the cancer cell specific energy metabolism by developing drugs and therapeutics.
