The Potential in Targeting Circadian Rhythms for Cancer Therapy
Current approaches to cancer therapy
There have been many advancements in cancer therapies such as the use of surgical interventions, chemotherapy and radiation. Surgery is the only method thus far that can be curative, although it is dependent on the entire tumour and all of its cells being successfully cut out. Chemotherapy, which employs certain chemicals to destroy cancer cells, can be used in conjunction with surgery. Alternatively, radiation therapy can be used to selectively shrink a tumour or damage cancer cells.1 Unfortunately, surgery can be highly invasive, while chemotherapy and radiation are known to have severe side effects when healthy cells are also affected. 2 Due to these limitations and side effects, new fields of cancer research are emerging to find safer, alternate therapies. One of these emerging fields focuses on targeting circadian rhythms.
Circadian rhythms and a possible connection to pancreatic cancer
Circadian rhythms are made up of genes and proteins that help regulate one's sleep, metabolism and cell division around a 24-hour cycle. Certain disruptions to this clock can lead to carcinogenesis by disturbing the mechanisms that allow cells to fix mutations in their genome, ensure the production of healthy cells, and allow mutated or damaged cells to die. When these mechanisms are disturbed, the cells can replicate rapidly, forming a benign or metastatic tumour. The regulation of circadian rhythms is highly complicated and occurs both in the brain, the central clock system, and in other organs around the body, the peripheral clock system, such as the pancreas.3 Thus, a potential driving factor for pancreatic cancer is this disruption in circadian rhythms.
The potential of targeting circadian rhythms is seen through current research on pancreatic cancer and can have potential applications to more rare forms. A rare subtype of pancreatic cancer is characterized by pancreatic neuroendocrine tumours, which only occur in 1-2% of all pancreatic cancers.4 Neuroendocrine tumours arise from neuroendocrine cells that receive signals from the nervous system to make and release hormones which have many functions throughout the body. These tumours not only physically degrade their surroundings, but they also tend to secrete an abnormal level of these hormones, which creates an imbalance and leads to additional problems.5 These tumours differ from pancreatic adenocarcinomas, which are tumours that arise from the exocrine tissues of the pancreas.6
Genes and proteins involved
Figure 1: Mechanism of circadian rhythms
A simplified diagram of the mechanism of circadian rhythms is shown in figure 1. In the morning, CLOCK and BMAL proteins bind to a promoter and activate the CRY and PER genes, thereby inducing the production of the CRY and PER proteins. These proteins accumulate in the cytoplasm of the cell throughout the day and form the CRY-PER complex in the evening. At night, this complex enters the nucleus of the cell and inhibits the CLOCK and BMAL proteins, stopping the production of CRY and PER proteins. As the night progresses, the CRY-PER complex starts to breakdown and eventually stops inhibiting the CLOCK-BMAL complex to start a new cycle in the morning.7 The functions of these various proteins and their role in creating the human biological clock are still being researched and debated. Most studies have only shown an association of these proteins with functions such as the sleep-wake cycle or with carcinogenesis when mutated.
In endocrine tumours, the most common proteins involved in carcinogenesis are the PER1 and CRY1 genes, whereas in pancreatic tumours, PER2 and BMA1L proteins are the most common.7,8 Studies have shown that a loss of the PER2 protein leads to increased resistance to chemotherapy and increases cell proliferation.9 Loss of PER2 is also associated with other cancers such as breast cancer.8 When BMAL1 expression is decreased, it suppresses the p53 pathway, thereby enhancing tumour growth. The p53 pathway is crucial in maintaining an antitumor effect and helps to stabilize the genome by allowing the cell to perform cellular arrest, temporarily or permanently, and apoptosis.10 As both endocrine tumors and pancreatic tumors have associated clock genes, a possible avenue for pancreatic endocrine tumor research is to investigate if these genes are involved in the presentation of this rare form of pancreatic cancer.
Current research
In pancreatic adenocarcinoma, Gemcitabine is a current chemotherapy treatment to help kill cancer cells. The effectiveness of this drug is enhanced when there is an increase in BMAL1, which helps to induce apoptosis in cancer cells. This has major implications in choosing when to administer treatment. However, this advantage is negated when there is an overexpression of a specific oncogenic microRNA that decreases BMAL1 and thus the effectiveness of this drug.11 This demonstrates the importance of understanding circadian rhythms and the proteins and nucleic acids involved. . If these details are not addressed, patient quality of life can be diminished, as well as the effectiveness of many current and potential cancer treatments for all types of pancreatic cancer.
Due to the significant impact of the peripheral clock system on the regulation of circadian rhythms, some researchers suggest that it can be a potential therapeutic target. As seen in the tissues affected by pancreatic cancer, there is a significant decrease in the genes associated with circadian rhythms compared to normal pancreatic tissue. Upregulating the expression of proteins such as BMAL1 or PER2 can potentially help decrease cell proliferation and increase the effectiveness of chemotherapy treatments.12 As observed with the use of the chemotherapy drug Gemcitabine, researchers should be aware of other interacting proteins and nucleic acids, such as microRNAs, to help address the problem more efficiently.
Looking towards the future
More research is needed in two areas to inform the development of targeting circadian rhythms as a viable alternative to cancer therapy. First, more research should be done on the effect of the loss, underexpression, and overexpression of the genes and proteins involved in circadian rhythms. Many studies have been able to show a correlation between cancer cell proliferation and an abnormal circadian rhythm gene or protein, but have not yet proposed a mechanism as to how the protein induces such an effect.7 Secondly, more research should be done on rare cancers, such as pancreatic neuroendocrine tumours that benefit from the identification of dysregulated clock genes as potential targets for cancer therapy. This will also allow for current treatments, such as chemotherapy, to be more effective and require shorter exposure, ultimately improving patients’ quality of life and decreasing risk of severe side effects.
Daksha Marfatia
Works Cited
1. Schimmack S. Pancreatic Neuroendocrine Neoplasms (pNENs). NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/pancreatic-neuroendocrine-neoplasms-pnens/. Published September 19, 2019.
2. Cheok CF. Protecting normal cells from the cytotoxicity of chemotherapy. Cell cycle (Georgetown, Tex.). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383581/. Published June 15, 2012.
3.Angelousi A, Kassi E, Ansari-Nasiri N, Randeva H, Kaltsas G, Chrousos G. Clock genes and cancer development in particular in endocrine tissues. erc. https://erc.bioscientifica.com/configurable/contentpage/journals$002ferc$002f26$002f6$002fERC-19-0094.xml. Published June 1, 2019.
4. Ohmoto A, Rokutan H, Yachida S. Pancreatic Neuroendocrine Neoplasms: Basic Biology, Current Treatment Strategies and Prospects for the Future. MDPI. https://www.mdpi.com/1422-0067/18/1/143. Published January 13, 2017.
5. Keener J, Sneyd J. Neuroendocrine Cells. SpringerLink. https://link.springer.com/chapter/10.1007/978-0-387-75847-3_9. Published January 1, 1970.
6. Schimmack S. Pancreatic Neuroendocrine Neoplasms (pNENs). NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/pancreatic-neuroendocrine-neoplasms-pnens/. Published September 19, 2019.
7. Angelousi A, Kassi E, Ansari-Nasiri N, Randeva H, Kaltsas G, Chrousos G. Clock genes and cancer development in particular in endocrine tissues. erc. https://erc.bioscientifica.com/configurable/contentpage/journals$002ferc$002f26$002f6$002fERC-19-0094.xml. Published June 1, 2019.
8. Garcia-Costela M, Escudero-Feliu J, Puentes-pardo JD, et al. Circadian Genes as Therapeutic Targets in Pancreatic Cancer. Frontiers in Endocrinology: Cancer Endocrinology. https://doi.org/10.3389/fendo.2020.00638. Published September 11, 2020.
9. Savvidis C, Koutsilieris M. Circadian Rhythm Disruption in Cancer Biology. BMC. https://doi.org/10.2119/molmed.2012.00077. Published July 17, 2012.
10. Jiang W, Zhao S, Jiang X, et al. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Letters. 2016;371(2):314-325. doi:10.1016/j.canlet.2015.12.002
11. Jiang W, Zhao S, Shen J, et al. The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance. Cell Death & Disease. 2018;9(2):149. doi:10.1038/s41419-017-0233-y
12. Garcia-Costela M, Escudero-Feliu J, Puentes-pardo JD, et al. Circadian Genes as Therapeutic Targets in Pancreatic Cancer. Frontiers in Endocrinology: Cancer Endocrinology. https://doi.org/10.3389/fendo.2020.00638. Published September 11, 2020.
Cite This Article:
Marfatia D., Chau J., Speagle M. The Potential in Targeting Circadian Rhythms for Cancer Therapy .Illustrated by S. Montakhaby. Rare Disease Review. March 2021.
DOI: 10.13140/RG.2.2.30264.67846
