Mitogen: Activators of Cell Proliferation Signaling

A Mitogen is a small molecule made of amino acids that signal a cell to divide and duplicate. This process, called mitosis, is fundamental to all types of life. When signaled by a mitogen, this process is referred to as Mitogenesis.

The mechanism by which mitogens signal cells is called a Mitogen-Activated Protein Kinase (MAPK). This term describes a pathway that is catalyzed/activated/signaled via a Mitogen. Mitogens are responsible for activating the first phase of cell replication (G1), acting as a sort of gateway messengers. Beyond this phase, cells do not require mitogenic activation to continue their replication cycle.

Exogenous Mitogens vs. Endogenous Mitogens

Mitogens can be either endogenous (made by our bodies) or exogenous (picked up from our environment). Examples of endogenous mitogens include Vascular Endothelial Growth Factor (VEGF)(2), Epidermal Growth Factor (EGF)(3), and Insulin-Like Growth Factor 1 (IGF-1)(4).

Exogenous mitogens are typically compounds that are also produced, to an extent, naturally within the human body either directly via metabolic processes or indirectly via things like bacteria or viruses. Examples include Lipopolysaccharides (LPS)(5), Nitric Oxide (6), and even Carbon Monoxide (7).

Role of Mitogens in Cancer

Mitogens are especially relevant to the progression of cancers. These compounds are largely responsible for the unchecked growth observed in tumor cells. In many cases, mutations or alterations in mitogenic processes are the main driving factor in cancer pathologies (8)(9)(10).

These types of altered mitogenic signaling processes can lead to positive feedback loops such that cancer cells are signaled to proliferate more quickly, which in turn produces more mitogenic signaling, which in turn causes faster proliferation, etc. Truly, a nasty cyclic process (11).

These same types of MAPK pathways associated with the mitogenic pathologies of cancers are often the targets of anticancer therapies meant to combat altered mitogenic signaling.

Anti-Mitogens

Compounds known as antimitogens can inhibit the natural, healthy replication of cells. For example, Transforming Growth Factor Beta (TGF-β) is known to “arrest” cell cycle signaling in ways that could help combat tumor growth (potentially)(12). Given the broad role of such cell cycle signaling, TGF-β should not be regarded as a cancer-specific therapy but, rather, simply one domain in which its activity is relevant.

As with mitogens, antimitogens are found as either endogenous or exogenous varieties as well. For example, emerging therapies for the treatment of Chronic Lyme disease like Suramin are known antimitogenic agents (13)(14)

References

1. Zheng, Jing et al. “Exogenous nitric oxide stimulate cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells.” Biology of reproduction vol. 74,2 (2006): 375-82. doi:10.1095/biolreprod.105.043190
2. Leung, D W et al. “Vascular endothelial growth factor is a secreted angiogenic mitogen.” Science (New York, N.Y.) vol. 246,4935 (1989): 1306-9. doi:10.1126/science.2479986
3. Lee, Sangjun et al. “Epidermal Growth Factor Receptor Signaling to the Mitogen-Activated Protein Kinase Pathway Bypasses Ras in Pancreatic Cancer Cells.” Pancreas vol. 45,2 (2016): 286-92. doi:10.1097/MPA.0000000000000379
4. Sasaoka, T et al. “Comparison of the insulin and insulin-like growth factor 1 mitogenic intracellular signaling pathways.” Endocrinology vol. 137,10 (1996): 4427-34. doi:10.1210/endo.137.10.8828504
5. Skidmore, B J et al. “Immunologic properties of bacterial lipopolysaccharide (LPS): correlation between the mitogenic, adjuvant, and immunogenic activities.” Journal of immunology (Baltimore, Md. : 1950) vol. 114,2 pt 2 (1975): 770-5.
6. Jing Zheng, et. al., Exogenous Nitric Oxide Stimulates Cell Proliferation via Activation of a Mitogen-Activated Protein Kinase Pathway in Ovine Fetoplacental Artery Endothelial Cells, Biology of Reproduction, Volume 74, Issue 2, 1 February 2006, Pages 375–382, doi: 10.1095/biolreprod.105.043190
7. Sethi, Jigme M et al. “Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells.” Antioxidants & redox signaling vol. 4,2 (2002): 241-8. doi:10.1089/152308602753666299
8. Schweppe, Rebecca E et al. “Distinct genetic alterations in the mitogen-activated protein kinase pathway dictate sensitivity of thyroid cancer cells to mitogen-activated protein kinase kinase 1/2 inhibition.” Thyroid : official journal of the American Thyroid Association vol. 19,8 (2009): 825-35. doi:10.1089/thy.2008.0362
9. Haagenson, Kelly K, and Gen Sheng Wu. “Mitogen-activated protein kinase phosphatases and cancer.” Cancer biology & therapy vol. 9,5 (2010): 337-40. doi:10.4161/cbt.9.5.11217
10. Matsuda, Kei et al. “Multiple mitogenic pathways in pancreatic cancer cells are blocked by a truncated epidermal growth factor receptor.” Cancer research vol. 62,19 (2002): 5611-7.
11. Singer, C.F., Kubista, E., Garmroudi, F. et al. Local feedback mechanisms in human breast cancer. Breast Cancer Res Treat 63, 95–104 (2000). https://doi.org/10.1023/A:1006430202101
12. Hocevar, B A, and P H Howe. “Mechanisms of TGF-beta-induced cell cycle arrest.” Mineral and electrolyte metabolism vol. 24,2-3 (1998): 131-5. doi:10.1159/000057360
13. Kathir, Karuppanan Muthusamy et al. “Understanding the mechanism of the antimitogenic activity of suramin.” Biochemistry vol. 45,3 (2006): 899-906. doi:10.1021/bi051389b
14. Parveen, Nuzhat, et al. “Suramin derivatives play an important role in blocking the interaction between FGF1 and FGFRD2 to inhibit cell proliferation.” European Journal of Medicinal Chemistry 206 (2020): 112656. doi: 10.1016/j.ejmech.2020.112656