Transcription
Hey there, mitochondri ACC. This is Dr. Casey Peer for another episode of "Cancer is a Mitochondrial Metabolic Disease." Today, we are going to finish the melatonin micro series on a very important topic: how melatonin completely reverses the Warburg effect and Warburg metabolism through a series of biochemical reactions that antagonize several steps of the process.
So, let's get into it. The first paper we're going to discuss today is called "Melatonin Inhibits Warburg-Dependent Cancer by Redirecting Glucose Oxidation to the Mitochondria: A Mechanistic Hypothesis." What it says here is that melatonin has the ability to intervene in the initiation, progression, and metastasis of some experimental cancers. A large variety of potential mechanisms have been advanced to describe the metabolic and molecular events associated with melatonin's interactions with cancer cells.
There is one metabolic perturbation that is common to a large number of solid tumors and accounts for the ability of cancer cells to actively proliferate, avoid apoptosis, and readily metastasize, i.e., they use cytosolic aerobic glycolysis (aka the Warburg effect) to rapidly generate the necessary ATP required for the high metabolic demands of cancer cells. There are several drugs referred to as glycolytic agents that cause cancer cells to abandon aerobic glycolysis and shift to a more conventional mitochondrial oxidative phosphorylation for ATP synthesis, as in normal cells. In doing so, glycolytic agents also inhibit cancer growth.
Herein, we hypothesize that melatonin also functions as an inhibitor of cytosolic glycolysis in cancer cells using mechanisms, i.e., downregulation of the enzyme pyruvate dehydrogenase kinase that intervenes with the conversion of pyruvate to acetyl-CoA in the mitochondria, as do other glycolytic drugs. In doing so, melatonin halts the proliferative activity of cancer cells, reduces their metastatic potential, and causes them to more readily undergo apoptosis or programmed cell death.
This hypothesis is discussed in relation to previously published reports, whereas melatonin is synthesized in the mitochondria of normal cells. We hypothesize that this synthetic capability is not present in cancer mitochondria because the depressed acetyl-CoA is necessary for the rate-limiting enzyme in melatonin synthesis. Finally, the ability of melatonin to switch glucose oxidation from the cytosol into the mitochondria also explains how tumors that become resistant to conventional chemotherapies are resensitized to the same treatment when melatonin is applied.
So, it's starting to paint the picture that melatonin, although it has diverse activities on cancer, is intimately involved in this Warburg phenomenon or Warburg metabolism, where cancer cells hyper-rely on glucose and glutamine for their survival, proliferation, and uncontrolled growth.
The next papers I want to discuss are "Anti-Effect of Melatonin: A Proposed Mechanism to Explain Its Inhibition of Multiple Diseases." What it says here is that glucose is an essential nutrient for every cell, but its metabolic fate depends on cellular phenotype. Normally, the product of cellular glycolysis, pyruvate, is transported into the mitochondria and irreversibly converted to acetyl-CoA by the pyruvate dehydrogenase complex. In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase (PDK). This altered metabolism is referred to as aerobic glycolysis or the Warburg effect and is common in solid tumors and other pathological cells.
Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and activation of the pentose phosphate pathway, which provides nucleotides. I'll also mention it provides the ability for cancer cells to have a higher capacity to produce glutathione and protect themselves against oxidative therapies. Molecules called glycolytic inhibitors block aerobic glycolysis and convert cells to a healthier phenotype. Glycolytic inhibitors often function by inhibiting hypoxia-inducible factor 1 alpha (HIF-1α), leading to PDC disinhibition, allowing for the inter-mitochondrial conversion of pyruvate to acetyl-CoA. Melatonin is a glycolytic inhibitor that converts diseased cells to their healthier phenotype.
This gets to a more interesting discussion because blocking glycolysis and blocking glutamine utilization is very interesting and necessary for cutting off fuel sources to cancer cells. But what these papers are suggesting is not only that melatonin is having an effect on the uptake of glucose, the utilization of glucose, and the creation of lactate, but what it's saying is that it's actually taking part in what appears to be a metabolic reprogramming from pathological Warburg metabolism back to a normal oxidative phosphorylation metabolism, which helps shut down the various vicious cycles that are going on. Fascinating!
The next paper, titled "Switching Disease Cells from Cytosolic Aerobic Glycolysis to Mitochondrial Oxidative Phosphorylation: A Metabolic Rhythm Regulated by Melatonin," shows that experimental data indicates that solid mammary tumors (breast cancer) depend on aerobic glycolysis during the day but likely revert to mitochondrial oxidative phosphorylation at night for ATP production. This conversion of diseased cells during the day to a healthier phenotype at night occurs under the control of circulating melatonin rhythm. When the nocturnal melatonin rise is inhibited by light exposure at night, cancer cells function in a diseased state 24/7.
The ability of melatonin to switch cancer cells, as well as other diseased cells (for example, Alzheimer's disease, fibrosis, hyperactivation of macrophages, etc.), from aerobic glycolysis to mitochondrial oxidative phosphorylation may be a basic protective mechanism to reduce pathologies. So, what this paper is essentially alluding to is that people who have cancer established in their body, in this case breast cancer, show a lot more growth and utilization of the Warburg metabolism during the day in particular. At night, if the person's melatonin cycle and release are somewhat preserved, it will actually stop the growth at night when melatonin is present.
That's fascinating because it shows that there is a clear on-and-off switch that melatonin can flip. It makes me, as a clinician, really curious about how to maximize patients' melatonin production and potentially supplement melatonin for patients. As in a prior paper, we showed that cancer cells appear to lose the ability to make endogenous melatonin, which is beneficial for cancer cells because now you've removed all semblance of a brake from their growth and metabolism.
This is where the nuance happens. In most people, we want to maximize melatonin production during the day and maximize circadian pineal release at night for the prevention of disease. However, in some pathologies, like cancer in particular, where the mitochondria are so damaged and they are not able to metabolically convert serotonin to melatonin due to metabolite issues associated with the Warburg metabolism, it would make sense to supplement exogenous melatonin. That's why a lot of clinics and integrative oncologists are recommending fairly high doses of melatonin throughout the day and night in order to maximize the inhibition and assist in metabolic reprogramming of cancer cells. Pretty cool!
Okay, so this next paper is titled "Melatonin Modulates the Warburg Effect and Alters the Morphology of Hepatocellular Carcinoma (HCC) Line Resulting in Reduced Viability and Migratory Potential." What it ultimately says here is that melatonin reduced cell motility and caused lamellar breakdown, membrane damage reduction, and microvillus reduction. Essentially, it says that there was reduced TGF and cadherin expression, which was further associated with the inhibition of the epithelial-mesenchymal transition (EMT) process. In relation to Warburg metabolism, melatonin reduced glucose uptake and lactate production by modulating intracellular lactate dehydrogenase activity. Our results indicate that melatonin can act upon pyruvate-lactate metabolism, preventing the Warburg effect, which may reflect in the cell architecture.
Let's see if we can take a look at this graph here and examine some of the beginnings of the basic mechanisms of how melatonin shuts down the Warburg effect. Number one, melatonin is going to shut down or reduce glucose uptake by cells. Remember, cancer cells uptake glucose about 10 to 30 times more than a normal cell. So, one of the important things that melatonin is doing is shutting down that excess uptake.
In addition to that, in order for glycolysis and fermentation to be complete, pyruvate (the end of glycolysis) is going to get converted to lactate. Lactate is going to be used for several different mechanisms, creating that tumor microenvironment, which can inhibit the immune system and snowball back upon HIF-1, creating that vicious cycle that propagates Warburg metabolism. So, we can see that if we were to shut down lactate production at two different levels—bringing in glucose and the actual activity of the LDH enzyme (lactate dehydrogenase)—that's going to be a net win for us in shutting down the Warburg effect.
In this paper titled "Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells," it states that when pyruvate dehydrogenase is inhibited during aerobic glycolysis or during the Warburg effect, and we'll show what mechanisms drive that process or during intracellular hypoxia, the deficiency of acetyl-CoA prevents mitochondria from making melatonin or synthesizing its own melatonin. That's the mechanism of how cancer cells can't produce their own melatonin, which also leads to further uncontrolled cell growth.
When cells experiencing aerobic glycolysis or hypoxia with diminished levels of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (aka pineal-derived), pathological cells convert to a more normal phenotype, leading to metabolic reprogramming of cancer cells back to normal cell function and supporting the transport of pyruvate into the mitochondria, thereby reestablishing a healthier mitochondrial metabolic physiology.
This is fascinating! This takes it another level again. Instead of just blocking glucose and glutamine like some medications and supplements, melatonin is taking it a step further and trying to reconvert a cancer cell back to a normal cell. So, let's try to unpack this graph here. Remember, glycolysis converts to pyruvate, and pyruvate converts to lactate. This is pathology unless you're doing a sprint or HIIT training or something like that. Remember, not forever; this is happening pathologically under the Warburg effect.
What's happening is melatonin is coming in and blocking several different things. Remember, we talked about it decreasing the amount of glucose uptake. It's blocking and inhibiting lactate dehydrogenase, so now you can't make lactate. Remember, lactate is driving HIF-1α and the pseudo-hypoxia. This is likely a graph that shows early on prior to the transformation of cancer. Melatonin is coming in, stimulating serine, and upregulating important enzymes that help shut down the excess oxidative stress.
Later on, once cancer is actually transformed, melatonin will actually increase oxidative stress, as we talked about in the past. We see here that 5-HT is converted to melatonin. This enzyme is not able to do its work because acetyl-CoA is not being made in the mitochondria because pyruvate is being blocked right here. This PDC enzyme (pyruvate dehydrogenase complex) is being inhibited by the Warburg metabolism. HIF-1 is upregulating this PDK enzyme (pyruvate dehydrogenase kinase), and what's happening is melatonin is actually inhibiting HIF-1 through various mechanisms. It's inhibiting PDK and ensuring that pyruvate, instead of getting converted into lactate, is getting converted into acetyl-CoA, and then melatonin's synthesis can be restored.
This is another paper titled "Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor." Ovarian cancer is the most lethal gynecologic malignancy, and melatonin has shown various anti-tumor properties. What it showed here is that the mitochondrial membrane potential of these ovarian cancer cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockouts increased its consumption, which means that at least some of the mechanism of action with the anti-Warburg metabolism happens through the melatonin receptor 1.
The interconversion of lactate to pyruvate increased after treatment with melatonin, so basically, pyruvate is getting into the mitochondria like it's supposed to when melatonin is given to the patients. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing, which means that some of these effects are independent of MT1 or melatonin receptor 1, and some of them are dependent.
This is another graph, and it's kind of giving a higher-level view of what's going on here. We have the MT1 receptor, we have glucose transporters, and what melatonin is doing is inhibiting the uptake of glucose so it can't participate in the Warburg metabolism or aerobic glycolysis. Melatonin is actually reducing the ability of pyruvate to convert to lactate, and it's actually ensuring that lactate is converted appropriately to pyruvate. Then, melatonin is blocking PDK (pyruvate dehydrogenase kinase), which has a blockade on PDC (pyruvate dehydrogenase complex).
These are astounding mechanisms, and it gets to the heart of what is really going on when it comes to cancer metabolism. We're blocking glucose uptake, we're blocking its utilization, and we're blocking lactate formation so that multiple vicious cycles and snowballs are being broken simultaneously.
This is just another paper showing a very similar thing where melatonin blocks this PDK. There are several other things that can block PDK; we talked about thiamine, and we haven't talked about DCA (dichloroacetate), but DCA also works upon that mechanism as well. It's cancer's utilization of PDK blocking PDC, which is a huge component of the Warburg metabolism that leads to progression, metastasis, drug resistance, and stemness.
This paper is titled "Melatonin Suppresses AKT/mTOR/S6K Activity, Induces Apoptosis, and Synergistically Inhibits Cell Growth with Sunitinib in Renal Cell Carcinoma via Reversing Warburg Effect." In conclusion, our results indicate that melatonin treatment reverses the Warburg effect and promotes intracellular ROS production, which leads to suppression of the AKT/mTOR/S6K signaling pathway, induction of cell apoptosis, and synergistic inhibition of cell growth with this monoclonal antibody, sunitinib, in renal cell carcinoma (RCC) cells.
As mentioned in the prior video, melatonin seems to be a team player, whether it be the conventional team or the alternative team. It is synergistic with chemotherapy, immunotherapy, radiotherapy, and mitochondrial metabolic therapies. Fascinating! Unbelievable! I hope that you're seeing the critical importance of melatonin at this point.
One of the other major mechanisms that has not been covered directly is that melatonin also directly shuts down HIF-1α stabilization. If you remember from prior videos, under normoxic or normal oxygen conditions, HIF-1α is degraded via the proteasome. What you're seeing here is that it is ubiquitinated and degraded by proteasomes. When there's hypoxia present or pseudo-hypoxia conditions that mimic low oxygen levels (and we've talked about those at length in the past), those conditions that mimic hypoxia or true hypoxia will stabilize HIF-1α. It will not get degraded; it will then get translocated to the nucleus and essentially drive Warburg metabolism.
So, not only is melatonin blocking glucose uptake, glucose utilization, the ability for cancer cells to utilize lactate, and the collapse of the tumor microenvironment (the acidic tumor microenvironment), but melatonin has direct effects on HIF-1α, which is truly the driver of the Warburg effect. Astounding!
So, we have the Warburg effect, increases in glucose transport, elevations in glycolysis, elevations in lactate dehydrogenase activity, elevations in PDK (pyruvate dehydrogenase kinase), and HIF-1 growth factors that are all affecting these pathways. Melatonin simply is a rockstar; it is the anti-Warburg miracle worker within our cells that blocks multiple pathways: HIF-1, AKT growth pathways, and C-MYC. It's going to block cell proliferation, angiogenesis, metastasis, and chemoresistance. It's going to remove the blockade on apoptosis and cell survival, and it's going to absolutely collapse cancer metabolism.
I'm going to end on this slide here because we, as clinicians, may not realize we have tools in our toolbox to help measure patients' melatonin levels. One of my favorite tests that I order is something called a Dutch test. A Dutch test has a lot of information on it, but one of the most important things that I've seen when it comes to disease prevention, reversal, and treatment is the urinary melatonin levels that we can measure on patients, as well as saliva melatonin levels that can be measured on patients at various times of the day.
So, we're not necessarily working in the dark here; there are tools available to clinicians. Your doctor can order these tests, and you can have a better answer regarding how much melatonin your body is making. That removes a lot of guesswork. Are the interventions that you're implementing—whether it be sun exposure, infrared exposure, or better blockade of blue light at night—having an impact? Well, we can test that directly.
If you remember right from one of the earlier slides, urinary melatonin metabolites have been shown to decrease the risk of breast cancer by 62% and 66%, respectively. So, this is not a joke; this is not something we want to mess around with. We want our melatonin levels to be maximized, and in some cases, if you have cancer, there are likely benefits to taking exogenous melatonin. The question is dosing, timing, and scheduling. As I've mentioned several times through several videos, this needs to be a conversation between you and your doctor to come up with a plan that best suits you, minimizes side effects, and maximizes benefits.
This concludes the melatonin micro series, and it has been extremely enjoyable for me to present this information to you. I hope that after this multiple-part video series, you can better appreciate and have some reverence for melatonin. I think a lot of us think of melatonin as a throwaway chemical that is something you can get at CVS, Walmart, or Whole Foods for pennies on the dollar and that it has very little benefit. It has a huge amount of benefit and a high degree of safety when taken at high doses. We also have the ability to make our own, and that should be first and foremost your main goal.
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