Beyond Diabetes: Exploring Metformin’s Promise in Prostate Cancer Therapy

By Rafaela Muniz de Queiroz 

Cancer and diabetes are two major contributors to mortality in patients, ranking among the top 10 causes of death worldwide by the World Health Organization (WHO). Both diseases pose a significant challenge to public health systems, representing a complex challenge that requires comprehensive strategies to reduce their impact on global mortality rates. Metformin, among other drugs, is the main first-line prescribed medication for the management of type 2 diabetes, and it is known for its efficacy and tolerability. Yet, metformin has gained attention for its role in other contexts, including cancer and cardiovascular disease.

Prostate cancer is a significant global health concern and a leading cause of cancer-related deaths among men. While treatments like radical prostatectomy (RP) and radiotherapy are effective for many patients, for others, the disease progresses leading to metastasis, which can be difficult to treat and is often fatal. Previous studies have pointed to metformin’s potential role in prostate cancer, but conflicting findings have led to an inconclusive verdict on the use of metformin for this disease. A recent breakthrough study headed by Alexandros Papachristodoulou from Dr. Abate-Shen’s group in the department of Molecular Pharmacology and Therapeutics at Columbia University Irving Medical Center, has shed light on a potential new avenue for the use of an anti-diabetic drug in the treatment of prostate cancer.

The prostate gland is susceptible to inflammation and oxidative stress, both of which can accelerate prostate cancer progression. Interestingly, oxidative stress influences the behavior of NKX3.1, a gene that plays a crucial role in protecting the prostate epithelium from cancer-related stress. In their work, Dr. Papachristodoulou and colleagues examine the interplay between NKX3.1 and the widely used diabetes drug metformin. The interplay between NKX3.1 and metformin are found in the mitochondria. NKX3.1 helps protect against harmful free radicals (unstable molecules that can damage cells by stealing electrons from other molecules) and supports normal mitochondrial function, while metformin has a known ability to regulate mitochondrial function and reduce oxidative stress.

The study published in 2024 used a comprehensive number of strategies to investigate its hypothesis, including in vitro work with the use of human prostate cancer cell lines, in vivo work using mouse models, and analysis of retrospective cohorts of patients. The authors show an impressive reduction of tumor size in mice under oxidative stress, by exposure to the herbicide Paraquat, and treated with Metformin. This difference was only seen if tumors did not express NKX3.1. They show that metformin treatment can fully rescue mitochondrial function that had been lost upon oxidative stress in prostate cancer cells lacking NKX3.1, pointing to a possible molecular mechanism for the effects seen in mice.

Moreover, the study analyzed the biochemical recurrence (BCR)-free survival, evaluated by the blood levels of PSA, the antigen used to diagnose and surveil prostate cancer in patients. This parameter is used in the clinic to show the percentage of patients that remain disease-free after RP over time. Utilizing data from two cohorts of patients, the researchers showed that those expressing low levels of NKX3.1 and taking metformin had a much higher rate of BCR-free survival compared to patients not taking the medication. The group of patients expressing high levels of NKX3.1 showed no difference in BCR-free survival when taking or not the drug. In addition, when the disease progression of a group of prostate cancer patients that have been followed up for up to 10 years was investigated, the authors observed that among the patients with low-NKX3.1, all patients treated with metformin evolved to have their disease classified more favorably during follow-up, while most patients not exposed to the medication had a worse development of the disease.

These findings open exciting possibilities for personalized treatment strategies for prostate cancer. It offers hope for a future where precision medicine plays a pivotal role in combating this disease and improving patient outcomes. By identifying patients with low NKX3.1 expression levels, clinicians may be able to tailor metformin therapy to those who are most likely to benefit, potentially improving patients’ quality of life and extending survival rates. While further research and clinical trials are needed to validate these findings, this study represents a significant step forward in understanding the biology of prostate cancer and exploring novel therapeutic avenues. 

Original paper

Reviewed by: Trang Nguyen, Erin Cullen

When mitochondria get stressed, our brain suffers: Linking mitochondrial dysfunction to neurodegeneration.

Imagine It’s a Saturday morning and you decide to drive upstate for a nice hike. While on the trail, you have a too-close encounter with a too-curious bear, leaving you panting, perplexed. This acute stress response (the famous fight-or-flight response) is extremely useful for us to better react to danger. The main hormones released during a stress response, glucocorticoids (GC), help prepare our body for the adverse situation we may encounter, giving us a better chance of survival.

Chronic stress it’s not so beneficial for us. In fact, it has profound detrimental effects on our bodies, and especially in our brain. There is increasing evidence that it can make our mitochondria (the powerhouse of the cell) function poorly, which can lead to damage in our neurons. Another way chronic stress can damage the brain is by inducing accumulation of the protein Tau, which can lead to neurodegenerative diseases such as Alzheimer’s disease. Tau itself poses an interesting biological conundrum: While it is normally found in the neuron’s microtubules (the cell’s scaffolding) in a healthy setting, it can start to form clumps (i.e, oligomerize) when a neuron becomes stressed or damaged, interfering with the neuron’s basic functions such as synaptic transmission and protein transport.

Scientists are still unsure how exactly GC cause Tau to oligomerize. Furthermore, while the impact of GC in mitochondria’s fitness is pretty well studied, the mechanisms driving such dysfunction, and its downstream consequences, are still poorly understood. Overall, to the scientific community, the molecular mechanisms linking GC exposure, mitochondrial dysfunction, and Tau pathology, are still unclear.

 In a recent study published in Brain, Columbia postdocs Dr. Fang Du and Dr. Qing Yu and colleagues investigated the causal relationship between these three important components of brain health, and found that GC directly precipitate mitochondrial dysfunction and drive Tau oligomerization. In a series of elegant experiments in both mouse models (in vivo) and neurons grown in petri dishes ( in vitro),experiments, the group led by Dr. Clarissa Waites demonstrated that found the mechanism by which GC exposure drives mitochondrial dysfunction and Tau oligomerization, and even discovered a potential treatment.

Figure 1- Graphical representation of the findings by Dr Du, Dr Yu, and colleagues. During Chronic stress, Glucocorticoids induce mitochondria dysfunction by increasing its permeability, which turn promotes Tau oligomerization and neurodegeneration. Figure created with Biorender.

 

 First, Dr. Waites’ group established the role of chronic GC exposure in mitochondrial fitness and pathogenic Tau accumulation in vivo. Using the widely used synthetic glucocorticoid dexamethasone (DEX), they demonstrated that GC induce mitochondrial dysfunction (increased permeability and lower respiratory capacity) and oligomeric Tau accumulation. Next, Drs. Du and Yu very cleverly employed in vitro experiments to demonstrate that DEX triggered mitochondrial dysfunction by increasing mitochondrial permeability: their research showed that GC exposure stimulates the opening of the mitochondrial permeability transition pore, a big, non-discriminant, pathological hole in the mitochondrial membrane that when open, greatly compromises its function. Most importantly, they found that GC triggers opening of the pore by activating its key component, the protein cyclophilin D. This key finding led Dr. Waites’ group to block cyclophilin D activation, either genetically (i.e. changing the DNA of the protein) or using drugs, with great success: cells where cyclophilin D activation was prevented were remarkably resilient to GC stress, and showed much lower levels of mitochondrial dysfunction and pathological Tau accumulation.

 Although this was an extremely exciting result by itself, it posed a problem moving forward: neither genetical nor pharmacological inhibition of cyclophilin D are currently viable therapeutic approaches, due to their poor bio-availability or invasive methods required to deliver the treatments. So what other approach could they use to also prevent mitochondrial pore opening, while still being clinically tractable? After some digging, Drs. Du and Yu found apo-cyanin, an orally-available inhibitor of mitochondrial respiration that could tackle GC-driven brain pathology while not directly targeting cyclophilin D. In line with their predictions, this drug was able to restore mitochondrial function and prevent Tau pathology in DEX-treated cells. Most importantly, they were also able to restore neuronal health, neuronal connectivity, and prevent anxious and depressive behavior associated with GC treatment.

 All of these experiments clearly demonstrated that GC-exposure triggers mitochondrial dysfunction and Tau accumulation, which could in turn promote the development of brain pathologies. How could they demonstrate, however, that targeting mitochondrial permeability is a feasible approach to treat common brain pathologies such as Alzheimer’s disease? To tackle this question, Dr Waites’ group made use of an ingenious technique, where they replaced all mitochondria in a test cell with those coming from an Alzheimer’s disease patient. Excitingly, in this model, treatment with mito-apocynin was sufficient to partially reverse mitochondrial dysfunction and Tau oligomerization found in the cells containing mitochondria from Alzheimer’s patients.

 Dr Waites’ group story is a hallmark out-of-the-box thinking, and clinical relevance. While their research clearly highlights mitochondrial damage induced by GC and cyclophilin D activation as a key trigger of Tau accumulation, the implications of this finding could be much broader:  How generalizable is this mechanism to other forms of brain disease such as ischemia, inflammation, or aging? As a matter of fact, cyclophilin D levels are elevated in Alzheimer’s patients, and its inhibition is protective in mouse models of sclerosis, Parkinson’s, and Alzheimer’s disease.

While this story provided incredible insight into the role of mitochondria in controlling brain pathology, many other questions remain unanswered.  For example, What is the exact mechanism by which mitochondrial dysfunction promotes pathogenic Tau accumulation? It is highly likely that these two events are intertwined, and that oligomeric Tau can also drive mitochondrial dysfunction.

 Despite the still-unknowns, it is clear that after this publication from Dr Waite’s lab, we should re-contextualize our middle-school textbooks: The mitochondria is the powerhouse of the cell, and during stress, the gate-keeper of our brain’s health.

Reviewed by: Trang Nguyen, Erin Cullen 

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