Targeting the cancer pathway of EMT (Epithelial to Mesenchymal Transition) via the invasive vimentin protein with four natural compounds as potential weapons to combat it.
A number of genes and signalling pathways are involved in cellular proliferation and growth and have been implicated in the pathophysiology of cancers. One important process that is involved in for instance, melanoma development and progression, is epithelial to mesenchymal transition1 EMT (Epithelial to Mesenchymal Transition).
What is EMT?
Endothelial to mesenchymal transition (EndoMT) is a process by which endothelial cells disaggregate, change shape, and migrate into the surrounding tissue. (Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue. Mesenchyme is a type of animal tissue comprised of loose cells embedded in a mesh of proteins and fluid, called the extracellular matrix.) This EndoMT process is characterized by the loss of endothelial cell markers and the expression of mesenchymal cell markers, such as vimentin2. In addition, a switch occurs from protective keratin to invasive vimentin-type filaments.
What is vimentin?
Vimentin is expressed at high levels in many epithelial tumors, including breast cancer, prostate cancer, melanoma, and lung cancer, and its expression is determinant for tumor growth, invasion, and poor prognosis and serves as potential target for cancer therapy3.
Target invasive vimentin
To counter EMT, we can possibly target vimentin 4 and potentially suppress it with Allium sativum via an anti-invasive /migratory effect. The garlic compound, ajoene’s ability to covalently bind to vimentin disrupts the vimentin network to exert anti-metastatic activity in cancer cells 5. Other natural compounds that target EMT via the anti-invasive/migratory effect in cancer cells are resveratrol6 and Withaferin A from Withania somnifera7 also known as Ashwagandha. A natural compound targeting vimentin is Ginsenoside 20(R)-Rg3 in Panax ginseng via EMT suppression 8.
The above studies involved cancer types that were not melanoma but demonstrate the usefulness of targeting the epithelial to mesenchymal transition via suppressing vimentin. A melanoma study 9 found in a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung via vimentin. (PARP is an enzyme that in humans is encoded by the PARP1 gene). Vimentin levels were down-regulated following PARP inhibition suggesting that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.
More about Garlic
A study of hairless mice found garlic supplementation ameliorates UV-Induced photoaging by regulating antioxidative activity10. The most common carcinogen, ultraviolet irradiation, appears to be inhibited by garlic,11. UV irradiation damages DNA and induces a specific defect in T-cell immunity, impairing the recognition of UV-induced malignancy. Most interestingly, oral garlic administration is found to protect from photoimmunosuppression12 . Garlic appears to stimulate immunity including macrophage activity, NK and killer cells, and lymphokine activated killer cells, and it increases production of IL-2,TNF, and INF-γ. These cytokines are associated with the beneficial Th1 antitumor response, which is characteristic of effective cancer immunotherapies13.
Are these safe to consume?
Natural compounds may interfere with cancer treatments of immunotherapy, chemotherapy and radiotherapy, so if you are thinking of taking these natural compounds, it is best to discuss with your oncologist prior to doing so. Garlic can reduce blood clotting, so it is best not to consume this before surgery.
To find out more about safety of consuming Garlic, go to https://www.mskcc.org/cancer-care/integrative-medicine/herbs/garlic
To find out more about safety of consuming Resveratrol, go to https://www.mskcc.org/cancer-care/integrative-medicine/herbs/resveratrol
To find out more about safety of consuming Ashwagandha, go to https://www.mskcc.org/cancer-care/integrative-medicine/herbs/ashwagandha
To find out more about safety of consuming Panax ginseng, go to https://www.mskcc.org/cancer-care/integrative-medicine/herbs/ginseng-asian
References
1. Paluncic J, Kovacevic Z, Jansson PJ, et al. Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. 2016;1863(4):770-784.
2. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nature Reviews Cancer. 2006;6(5):392-401.
3. Satelli A, Li S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cellular and molecular life sciences : CMLS. 2011;68(18):3033-3046.
4. Strouhalova K, Přechová M, Gandalovičová A, Brábek J, Gregor M, Rosel D. Vimentin Intermediate Filaments as Potential Target for Cancer Treatment. Cancers (Basel). 2020;12(1):184.
5. Kaschula CH, Tuveri R, Ngarande E, et al. The garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cells. BMC Cancer. 2019;19(1):248.
6. Ji Q, Liu X, Han Z, et al. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer. 2015;15(1):97.
7. Thaiparambil JT, Bender L, Ganesh T, et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Int J Cancer. 2011;129(11):2744-2755.
8. Kim Y-J, Choi W-I, Jeon B-N, et al. Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial–mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. Toxicology. 2014;322:23-33.
9. Rodríguez MI, Peralta-Leal A, O’Valle F, et al. PARP-1 regulates metastatic melanoma through modulation of vimentin-induced malignant transformation. PLoS Genet. 2013;9(6):e1003531.
10. Kim HK. Garlic Supplementation Ameliorates UV-Induced Photoaging in Hairless Mice by Regulating Antioxidative Activity and MMPs Expression. Molecules. 2016;21(1):70.
11. Reeve VE, Bosnic M, Rozinova E, Boehm-Wilcox C. A garlic extract protects from ultraviolet B (280-320 nm) radiation-induced suppression of contact hypersensitivity. Photochem Photobiol. 1993;58(6):813-817.
12. Lamm DL, Riggs DR. Enhanced Immunocompetence by Garlic: Role in Bladder Cancer and Other Malignancies. The Journal of Nutrition. 2001;131(3):1067S-1070S.