Research Summary: Statins, the lipid-lowering drugs, exhibit anti-tumor properties by targeting a crucial oncogenic pathway in colorectal cancer. Mechanistically, major components of the aberrant Wnt/β-catenin signaling are downregulated in a mevalonate pathway-dependent manner.
Author interview
Sneha Tripathi is continuing her quest for novel cancer treatment regimens with her expertise in proteomics, among many. She is also a proficient visual science communicator, as storytelling is her passion!
Lab: Prof Sanjeev Galande, Indian Institute of Science Education and Research, Pune; and Shiv Nadar University Delhi-NCR
Website: https://www.sglabepigenetics.com/
Twitter: https://x.com/SanjeevSaGa
What was the core problem you aimed to solve with this research?
Statins inhibit cholesterol biosynthesis via the mevalonate pathway and are widely used to reduce blood cholesterol levels in patients with hyperlipidemia. Because cholesterol biosynthesis influences several downstream processes—including protein synthesis, free fatty acid production, ubiquinone synthesis, and protein isoprenylation, all of which play key roles in cellular signaling—inhibiting this central pathway raises questions about the pleiotropic effects of statins. Earlier statin formulations were associated with side effects such as nausea and weight loss, which were mitigated in later synthetically produced versions. The statins currently available in the market allow for better drug assimilation with minimal side effects, and we used these latest formulations in our study.
The core problem we sought to resolve was to convincingly demonstrate that statins have functions beyond lipid-lowering. This does not imply that we are validating their pleotropic effects; rather, it is important to distinguish between nonspecific side effects and specific, targeted mode of action on other cellular pathways.
With this study we unequivocally demonstrate that statins target Wnt/β-catenin signaling specifically in colorectal cancer cells as well as in whole animal model. Furthermore, we provide direct evidence establishing statins as anti-tumor drugs and present a possibility of including them in the routine cancer treatment regime.
How did you go about solving this problem?
The first experiment we performed was to validate the effect of statins on the cholesterol biosynthesis pathway by performing a targeted lipidomics. We observed that cholesterol and its derived oxysterols were indeed significantly reduced upon statin treatment, which is expected. However, when we observed other free fatty acids and prostaglandins levels, only the ones known for their oncogenic role showed reduction. Most of them were not altered at all, suggesting a highly specific effect of statins on lipids as well.
Similarly, when we analyzed the total set of RNAs (transcriptome) and proteins (proteome) expressed in the colorectal cancer cells upon statin treatment, we specifically observed the downregulation of oncogenic transcription factors and gene products. The most striking observation was the significant downregulation of Wnt pathway. Interestingly, there have been many links reported between the Wnt signaling and cholesterol biosynthesis pathway, which might explain why we observed an effect specifically on Wnt signaling. Further, the cholesterol-responsive genes were upregulated in response to the reduction of cholesterol. The feedback loop mechanism that kicked in when the cells sensed low cholesterol resulted in the increased expression of cholesterol biosynthesis genes as if the cells tried to replenish their stock! This observation validated that indeed the canonical mode of action of statins was intact in the cells, along with its specific effect on the oncogenic pathways, supporting a tumor suppressive phenotype.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Colorectal cancer can be caused by many factors, like improper diet, chronic or long-term inflammation in the gut, and at times due to high cholesterol levels in blood, which has been shown by number of studies to be one of the causes for cancer development. What if we could monitor and manage one of the above causes, like the high blood cholesterol levels which can tell us a lot about our gut in time?
Statins are the most commonly prescribed drugs for lowering high cholesterol. But how do elevated cholesterol levels relate to colorectal cancer? Could there be a molecular mechanism that explains how statins might be effective in treating colorectal cancer? This is precisely the question we set out to explore.
Since statins have been used in lowering cholesterol levels, it will also help lower the cholesterol for tumor cells which acts as a fuel for its metabolism. Therefore, the one-way statins can work is by cutting off the fuel, which will control the growth of the ever-hungry cancer cells. However, there is an alternative mode that we reported.
We observed that statins target the cellular pathway responsible for tumor progress, namely the Wnt/β-catenin signaling. This signaling has many cancer-causing proteins in large numbers that dictate the cells to become cancerous. Statins lower the levels of these proteins and help attenuate the progression of cancer. In our experiments using mice, wherein we induced tomors and then treated them with statins, we observed that a few mice in the treated group did not develop tumor at all, whereas, the rest formed a very small tumor as compared to the control mice without statin treatment.
There are two key points to understand regarding statins. First, they hold potential as a repurposed drug, transitioning from their conventional use in lowering blood cholesterol to being incorporated into cancer therapy. Second, statins alone cannot ‘cure’ cancer. While many people take statins to manage high blood cholesterol, their use does not guarantee cancer prevention. Statins can help regulate cholesterol levels and may aid in the early diagnosis of colorectal cancer. Based on our study, we propose that statins could be added to the treatment regimen for colorectal cancer, as they have demonstrated direct benefits.
What are the potential implications of your findings for the field and society?
The major challenge with colorectal cancer is its late diagnosis. In most cases, the disease is detected only after it has advanced to stages involving lymph node metastasis or secondary tumor formation in organs such as the liver. At this progressed stage, treatment options are limited, typically involving surgical removal of tumors followed by chemotherapy. Currently, no drugs are available that specifically target oncogenic pathways to slow tumor progression. Since statins are already part of established pharmacological use, if we can demonstrate that they improve disease management when combined with existing treatment protocols, they could be incorporated into clinical practice more rapidly than novel formulations, as they are already approved drugs.
Physiologically, numerous studies have reported correlations between abnormally high blood cholesterol levels and an increased incidence of colorectal cancer. This further underscores the importance of our study in colorectal cancer patients, as it opens possibilities for early diagnosis, and in some cases, even cancer prevention.
With the help of this study, we wish to establish that statins can be used in combination with chemotherapy to yield better outcomes for the patient. Our ultimate goal was to take this research from bench to bedside, backed with a solid mechanism for its mode of action.
“This study demonstrates the potential of repurposing statins for cancer therapy. It is gratifying to witness the rapid translation of these laboratory findings to clinical application. — Prof Sanjeev Galande”
What was the exciting moment during your research?
The most exciting moment in our research was when we discovered a correlation between the expression of a Wnt-responsive factor with EMT (epithelial to mesenchymal) phenotype, which was reversed upon statin treatment. SATB1 (Special AT-rich Binding protein), is a chromatin organizer that has been shown to be one of the major components of the Wnt/β-catenin signaling. SATB1 is upregulated in colorectal cancer cells, however, upon statin treatment, it is downregulated.
The first interesting observation was that the three dimensionally (3D) grown spheroids, generated from a monolayer of colorectal cancer cells grown in two dimensions (2D), exhibited higher expression of SATB1 as well as vimentin, a known mesenchymal marker. This validated the higher tumorigenic capacity of the spheroids as well as increased expression of the oncogenic protein SATB1 in them.
Another noteworthy observation emerged when we treated the spheroids with statin. We found that SATB1 levels were significantly reduced, while the epithelial marker E-cadherin was highly expressed. This indicates that statin not only affected Wnt pathway components but also appeared to reverse the mesenchymal-to-epithelial phenotype. Physically, the spheroids disintegrated on the matrix following statin treatment, further supporting a reversal in cell type.
Paper reference: Tripathi S., Gupta E., Naik R., Khare S., Mir R., Kamat S., Galande S. Statins exhibit anti-tumor potential by modulating Wnt/β-catenin signaling in colorectal cancer. Oncotarget. 2025; 16: 562-581. Retrieved from https://www.oncotarget.com/article/28755/
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