Adithi Voleti ’23 and Anonymous

Alongside the green matcha lattes and swirly chai lattes, a new, trendy, favorite has been added to coffee shop menus: golden lattes (Figure 1). These yellow lattes feature a special ingredient that gives them their warm hue: turmeric. As daughters of Indian immigrant parents, turmeric is quite a familiar ingredient. It is a staple in the Indian kitchen that is frequently used in many home remedies. In fact, in Ayurveda (Indian natural medicine) and ancient Chinese medicine, turmeric is a popular ingredient for various remedies ranging from digestive issues to healthier skin. Recent scientific studies are now beginning to validate and recognize the clinical value of turmeric. The active ingredient in turmeric is curcumin, and it has been shown to have beneficial effects including altering our susceptibility to colon cancer. 

Figure 1. Starbucks Advertisement for Golden Turmeric Latte

Curcumin (Figure 2) is a plant-based compound extracted from the turmeric plant root 10. It has been a vital compound since ancient times for medicinal use and is now a common spice worldwide4. Additionally, curcumin is used in Asian countries to make delicacies and cosmetics. Spreading throughout South Asia, it is used as an antiseptic or anti-inflammatory agent. Traveling across the Atlantic Ocean, turmeric is added to foods and made into supplements in the Western Hemisphere. In fact, the US Food and Drug Administration (FDA) approved curcumin as “Generally Recognized As Safe” (GRAS)4. 

Figure 2. Structure of Curcumin 

Studies on curcumin focused on colon cancer because curcumin is found in our food. Hence, when digestion occurs, curcumin is present at higher levels in the colon compared to other organs3. Therefore, because curcumin is found at higher levels in the colon, it is a potential candidate for colon cancer therapy. But why highlight colon cancer, specifically? As of 2022, colon cancer is the third most common cancer globally and impacts the lower digestive tract starting in the colon or rectum (Figure 3)12. While digesting food, the colon is important for absorbing water, nutrients, and electrolytes for the body’s use. Unfortunately, the current treatments for colon cancer mostly consist of chemotherapy which can be quite grueling for patients5. With curcumin’s positive reputation, it is mind-blowing to consider how this nutritional, digestive supplement can help mitigate colon cancer.

Figure 3. Colon Cancer Diagram
Source

When thinking about treating cancer, it comes down to the foundation of our cells: our genes. With our genes, there is an additional dimension to consider called our epigenome. If we think of our genes as forming an electrical circuit, the epigenome is the presence or absence of electrical tape over the switches in the circuit. Therefore, the epigenome is another layer of information that influences how our genes are expressed. An example of an epigenetic change, or electrical tape, is the methylation of genes which locks certain gene switches in the off position, making them inaccessible to be turned on. So, biologically, methylation makes genes harder to access, leading to less gene activation. In 2013, a study found that curcumin decreased cancer growth due to reduced methylation of genes7. In other words, curcumin removed the layers of tape and switched on certain genes involved in normal cell functioning. By turning genes on that are needed for normal functioning, curcumin is essentially reverting cancerous cells back to more normal cell behavior. In particular, the study found that reduction in methylation occurred at specific locations, rather than everywhere, on the genome. These specific gene locations are called CpG islands7. These islands are like the control panel for a gene circuit wherein methylation of a CpG island tapes the switches off and reducing the methylation of a CpG island turns the switches on (Figure 4). Here, the scientists found that curcumin specifically reduces methylation at CpG islands by acting as a hand to remove electrical tape from the control panel and flip the gene switch from off to on (Figure 5). Thus, curcumin changes our epigenome by turning on certain genes in a specific manner which has anti-cancer effects. 

Figure 4. CpG Island Regulation on Gene Expression 

As described above, curcumin reduces methylation at the control panels, or CpG islands, of specific genes. An example of this is the DLEC1 gene which prevents cells from growing uncontrollably and ultimately forming cancerous tumors 15. If this gene is silenced, cells divide and grow faster akin to cancer cells. Since switching DLEC1 off transforms cells to be cancerous, switching DLEC1 on is anti-cancerous. In colon cancer cells, DLEC1 is 95.8% methylated at its CpG islands 15. Since methylation tapes switches off in the CpG control panel, DLEC1 is 95.8% turned off. Removing the tape and reversing these off switches can turn DLEC1 back on, which may help reverse colon cancer. This is where curcumin comes in! Treating cells with curcumin reduces methylation at the CpG sites for DLEC1 like a hand removing tape from the control panel to turn the DLEC1 gene switch on as previously mentioned3. This prevents cells from uncontrollably multiplying into a tumor. In addition to observing whether the gene itself is turned on or off, we can also examine what happens to compounds that gene codes for. For example, in the electricity analogy, changes in the “control panel” ultimately change whether light bulbs turn on or off. In a gene circuit, the lightbulb is known as mRNA. After treatment with curcumin, the scientists found that the amount of DLEC1 mRNA also increased, or the number of light bulbs turned on increased3. Therefore, curcumin not only turns DLEC1 gene switch on at the control panel (CpG islands), but also turns on more lightbulbs or increases DLEC1 mRNA levels. By testing both CpG methylation and mRNA levels, scientists provide a more supported and compelling argument on curcumin’s effectiveness. In summary, it is observed that curcumin has anti-cancer effects by reducing methylation at specific locations called CpG islands to turn on cancer-suppressing genes such as DLEC13,7. 

Figure 5. Curcumin Affecting Methylation 

Our body is made up of numerous, different gene circuits that have been found to regulate different properties of colon cancer. Previously, we looked at one gene circuit that consisted of the DLEC1 gene and observed how turning it on decreased cancer growth. Now, let us explore another circuit that can mitigate cancer by regulating microRNAs. In cancer cells, certain gene circuits are more active than normal which results in increased gene expression and increased tumor-forming mRNA levels, or in our analogy, an excessive amount of lightbulbs being turned on. But microRNAs are a solution to reduce the number of light bulbs being turned on. Biologically, microRNAs are a type of molecule that pairs up with mRNA like two strands of a zipper. When the zipper is closed, the mRNA cannot function to promote excess cell growth. Analogically, while CpG islands regulate lightbulb expression from afar, microRNAs regulate lightbulb expression by acting directly on the bulb itself like a lightbulb cover. In cancer, there are lower levels of certain microRNAs, leading to excess mRNA levels which promote excess cell growth and tumor formation. However, curcumin treatment reverses this by increasing the expression of certain microRNAs, namely miR-3411. Curcumin allows for this by removing the tape, or reducing methylation, from the CpG islands that are part of the microRNA gene circuit. This turns on microRNA genes to produce microRNAs which can “zip-up” and inhibit cancer-promoting mRNAs. Or, in relation to the analogy, there are more lightbulb covers over the lightbulbs. Interestingly, this increase in microRNAs also plays a role in decreasing chemotherapy resistance. Chemotherapy resistance develops when cancer cells are no longer harmed by chemotherapy drugs, rendering these drugs therapeutically ineffective. Because certain microRNAs are not expressed as highly in cancer cells, it makes these cancer cells more resistant to chemotherapies. These resistant cancer cells are particularly dangerous! However, with curcumin treatment, these cells lose their resistance and become more sensitive to chemotherapy 13. Again, curcumin reduces this resistance by increasing certain microRNAs levels (ie. microRNA-200c). These two examples highlight how curcumin treatment could mitigate cancer by directly increasing microRNAs. 

Figure 6. Curcumin affecting microRNA (miRNA), and miRNA affecting mRNA

Taking everything together, curcumin has anti-cancer properties through two overarching epigenetic “circuits.” One “circuit” is reduced methylation, or turning on, certain genes that have anti-cancer effects in cancer cells. Another “circuit” increases certain microRNA levels to inhibit cancer-inducing mRNA and reduce cancer cells’ chemotherapy resistance. While there is extensive scientific literature on curcumin effects, a majority of the findings are in vitro. This means that curcumin effects were tested in colon cancer cells on lab dishes, as opposed to in vivo, which would use model organisms such as mice. Conducting curcumin studies in mice is beneficial because mice and humans share a lot of genes, increasing the applicability of curcumin as a potential human treatment1. Thus, to elevate curcumin’s significance and perhaps extend its implications as an alternative, non-invasive treatment, more in vivo studies should be conducted. In other words, further curcumin research is needed, but it holds a lot of promise to improve colon cancer treatments. Interestingly, the effects of curcumin are not limited to colon cancer, and the anti-cancer mechanisms found in colon cancer are found in other prevalent cancers, such as lung cancer14. Additionally, the implications of curcumin can extend beyond mitigating cancer. Akin to ancient times, recent research has found mechanisms of how curcumin can enhance our immune system response and reduce inflammation14. Lastly, curcumin is chemically similar to other molecules found in popular drinks, such as green tea. So synergistic relationships between these molecules can be further investigated to study the impacts of diet on improving health. As Hippocrates, a Greek physician and renowned medical figure, once stated: “food may be used instead of medicine as cure remedy.” With this apt quote for discussing curcumin and colon cancer, it is profound to see that what we eat goes beyond just flavor and energy!

References

  1. Anonymous. (2010, July 23). Why Mouse Matters. Genome.gov. Retrieved from https://www.genome.gov/10001345/importance-of-mouse-genome 
  2. Anonymous. (2022, February 14). Colorectal Cancer – Statistics. Cancer.Net. Retrieved from https://www.cancer.net/cancer-types/colorectal-cancer/statistics 
  3. Guo, Y., Shu, L., Zhang, C., Su, Z. Y., & Kong, A. N. (2015). Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochemical pharmacology, 94(2), 69–78. https://doi.org/10.1016/j.bcp.2015.01.009
  4. Gupta, S. C., Patchva, S., & Aggarwal, B. B. (2013). Therapeutic roles of curcumin: lessons learned from clinical trials. The AAPS journal, 15(1), 195–218. https://doi.org/10.1208/s12248-012-9432-8
  5. Hollande, F., Pannequin, J., & Joubert, D. (2010). The long road to colorectal cancer therapy: searching for the right signals. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 13(1-2), 44–56. https://doi.org/10.1016/j.drup.2009.01.002
  6. Khan, M. I., Rath, S., Adhami, V. M., & Mukhtar, H. (2018). Targeting epigenome with dietary nutrients in cancer: Current advances and future challenges. Pharmacological research, 129, 375–387. https://doi.org/10.1016/j.phrs.2017.12.008
  7. Link, A., Balaguer, F., Shen, Y., Lozano, J. J., Leung, H. C., Boland, C. R., & Goel, A. (2013). Curcumin modulates DNA methylation in colorectal cancer cells. PloS one, 8(2), e57709. https://doi.org/10.1371/journal.pone.0057709
  8. Link, A., Balaguer, F., & Goel, A. (2010). Cancer chemoprevention by dietary polyphenols: promising role for epigenetics. Biochemical pharmacology, 80(12), 1771–1792. https://doi.org/10.1016/j.bcp.2010.06.036
  9. Nasir, A., Bullo, M., Ahmed, Z., Imtiaz, A., Yaqoob, E., Jadoon, M., Ahmed, H., Afreen, A., & Yaqoob, S. (2020). Nutrigenomics: Epigenetics and cancer prevention: A comprehensive review. Critical reviews in food science and nutrition, 60(8), 1375–1387. https://doi.org/10.1080/10408398.2019.1571480
  10. Naturally, T. (2019, May 1). Story from Terry Naturally: The ways turmeric and curcumin differ might surprise you. USA Today. Retrieved from https://www.usatoday.com/story/sponsor-story/terry-naturally/2019/05/01/ways-turmeric-and-curcumin-differ-might-surprise-you/3541923002/
  11. Roy, S., Levi, E., Majumdar, A. P., & Sarkar, F. H. (2012). Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF. Journal of hematology & oncology, 5, 58. https://doi.org/10.1186/1756-8722-5-58
  12. The American Cancer Society. (2020, June 29). What Is Colorectal Cancer? | How Does Colorectal Cancer Start? Retrieved from https://www.cancer.org/cancer/colon-rectal-cancer/about/what-is-colorectal-cancer.html#:%7E:text=Colorectal%20cancer%20starts%20in%20the,to%20grow%20out%20of%20control.
  13. Toden, S., Okugawa, Y., Jascur, T., Wodarz, D., Komarova, N. L., Buhrmann, C., Shakibaei, M., Boland, C. R., & Goel, A. (2015). Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis, 36(3), 355–367. https://doi.org/10.1093/carcin/bgv006
  14. Weng, W., & Goel, A. (2022). Curcumin and colorectal cancer: An update and current perspective on this natural medicine. Seminars in cancer biology, 80, 73–86. https://doi.org/10.1016/j.semcancer.2020.02.011
  15. Ying, J., Poon, F. F., Yu, J., Geng, H., Wong, A. H., Qiu, G. H., Goh, H. K., Rha, S. Y., Tian, L., Chan, A. T., Sung, J. J., & Tao, Q. (2009). DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers. British journal of cancer, 100(4), 663–669. https://doi.org/10.1038/sj.bjc.6604888

Featured Image Source

Cornish, R. (2021, August 9). Everything you need to know about … turmeric. Good Food. Retrieved December 31, 2022, from https://www.goodfood.com.au/recipes/news/turmeric-everything-you-need-to-know-20210803-h1xmuh