Synergistic Targeting of Krüppel-like factor and r Related Signaling Pathways by Metadichol: A Multidimensional Anticancer Strategy
Main Article Content
Abstract
Metadichol, a nanoemulsion of long-chain lipid alcohols, demonstrates a unique capacity to modulate the expression of the entire (KLF) transcription factor family (KLF1–KLF18) in human peripheral blood mononuclear cells (PBMCs) in a concentration-dependent manner. Using qRT-PCR and Western blot techniques, at 1 ng/ml, Metadichol downregulated 14 of 18 KLFs while selectively upregulating KLF4, KLF15, KLF17, and KLF18—factors often implicated in tumor suppression or context-dependent cancer regulation. Lower and higher concentrations produced distinct, biphasic expression patterns, indicating complex dose-dependent regulatory mechanisms. Beyond the KLF family, previous work has shown that metadichol influences interconnected signaling networks involving nuclear receptors, sirtuins, Toll-like receptors, circadian genes, and key tumor suppressors such as TP53 and Klotho. Network analysis suggests that this broad-spectrum modulation may overcome compensatory mechanisms within cancer cells, offering synergistic antitumor effects. The scope of this paper is to comprehensively analyze Metadichol and its dose-dependent regulation of KLFs and related pathways, while the purpose is to establish Metadichol as a multitarget anticancer agent capable of overcoming compensatory mechanisms in cancer cells, with potential applications in other diseases driven by transcriptional dysregulation. By simultaneously targeting multiple pathways, Metadichol offers a novel integrative approach to enhance therapeutic efficacy compared to single-pathway interventions.
Keywords:
Metadichol KLF, Toll-like receptors, nuclear receptors, sirtuins, circadian genes, Klotho, TP53, FOXO1, PPARGC1A, telomerase, long-chain lipid alcohols
Article Details
How to Cite
RAGHAVAN, Palayakotai R.
Synergistic Targeting of Krüppel-like factor and r Related Signaling Pathways by Metadichol: A Multidimensional Anticancer Strategy.
Medical Research Archives, [S.l.], v. 13, n. 6, june 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6583>. Date accessed: 17 july 2025.
doi: https://doi.org/10.18103/mra.v13i6.6583.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Black AR, Black JD, Azizkhan-Clifford J. Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol. 2001;188(2):143-160. doi:10.1002/jcp.1111
4. Alder JK, Georgantas RW III, Hildreth RL, et al. Krüppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol. 2008;180(8):5645-5652. doi:10.4049/jimmunol.180.8.5645
5. Mao A, Zhou X, Liu Y, Ding J, Miao A, Pan G. KLF8 is associated with poor prognosis and regulates glycolysis by targeting GLUT4 in gastric cancer. J Cell Mol Med. 2019;23(8):5087-5097. doi:10.1111/jcmm.14378
6. Sebzda E, Zou Z, Lee JS, Wang T, Kahn ML. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat Immunol. 2008;9(3):292-300. doi:10.1038/ni1565
7. Papadakis KA, Krempski J, Svingen P, et al. Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation. Am J Physiol Gastrointest Liver Physiol. 2015; 309(11):G900-G909. doi:10.1152/ajpgi.00309.2015
8. Mallipattu SK, Estrada CC, He JC. The critical role of Krüppel-like factors in kidney disease. Am J Physiol Renal Physiol. 2017;312(2):F259-F265. doi:10.1152/ajprenal.00550.2016
9. Papadakis K, Krempski J. Krüppel-like factor KLF10 regulates intestinal macrophages and innate immune colitis. Inflamm Bowel Dis. 2014;20(suppl 1):S106. doi:10.1097/01.MIB.0000456963.59724.80
10. Dabravolski SA, Sukhorukov VN, Kalmykov VA, Grechko AV, Shakhpazyan NK, Orekhov AN. The role of KLF2 in the regulation of atherosclerosis development and potential use of KLF2-targeted therapy. Biomedicines. 2022;10(2):254. doi:10.3390/biomedicines10020254
11. Sathanoori R, Rosi F, Gu BJ, et al. Shear stress modulates endothelial KLF2 through activation of P2X4. Purinergic Signal. 2015;11(1):139-153. doi:10.1007/s11302-014-9442-3
12. Liu C, Shen M, Tan WLW, et al. Statins improve endothelial function via suppression of epigenetic-driven EndMT. Nat Cardiovasc Res. 2023;2:467-485. doi:10.1038/s44161-023-00267-1
13. Tugal D, Jain MK, Simon DI. Endothelial KLF4: crippling vascular injury? J Am Heart Assoc. 2014;3(1):e000769. doi:10.1161/JAHA.113.000769
14. Heard ME, Velarde MC, Giudice LC, Simmen FA, Simmen RCM. Krüppel-like factor 13 deficiency in uterine endometrial cells contributes to defective steroid hormone receptor signaling but not lesion establishment in a mouse model of endometriosis. Biol Reprod. 2015;92(6):140. doi:10.1095/biolreprod.115.130260
15. Heard ME, Simmons CD, Simmen FA, Simmen RC. Krüppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis. Endocrinology. 2014;155(4):1532-1546. doi:10.1210/en.2013-1947
16. Homeister AW, Patterson C. Zinc fingers in the pizza pie. Circ Res. 2008;103(7):665-667. doi:10.1161/CIRCRESAHA.108.185763
17. Yang Y, Goldstein BG, Chao HH, Katz JP. KLF4 and KLF5 regulate proliferation, apoptosis, and invasion in esophageal cancer cells. Cancer Biol Ther. 2005;4(11):1216-1221. doi:10.4161/cbt.4.11.2090
18. Brown AR, Simmen R, Simmen F. Suppression of insulin-induced fatty acid synthase gene expression and colon cancer cell proliferation by members of the Krüppel-like family of transcription factors. Cancer Prev Res. 2011;4(10 Suppl):A44.
19. Bieker JJ. Krüppel-like factors: three fingers in many pies. J Biol Chem. 2001;276(37):34355-34358. doi:10.1074/jbc.R100043200
20. Pang CJ, Lemsaddek W, Alhashem YN, et al. Krüppel-like factor 1 (KLF1), KLF2, and Myc control a regulatory network essential for embryonic erythropoiesis. Mol Cell Biol. 2012;32(13):2628-2644. doi:10.1128/MCB.00104-12
21. Kalra IS, Alam MM, Choudhary PK, Pace BS. Krüppel-like factor 4 activates HBG gene expression in primary erythroid cells. Br J Haematol. 2011; 154(2):248-259. doi:10.1111/j.1365-2141.2011.08710.x
22. Vinci M, Greco D, Treccarichi S, et al. Bioinformatic evaluation of KLF13 genetic variant: implications for neurodevelopmental and psychiatric symptoms. Genes. 2024;15(8):1056. doi:10.3390/genes15081056
23. Shaverdashvili K, Padlo J, Weinblatt D, et al. KLF4 activates NFκB signaling and esophageal epithelial inflammation via the Rho-related GTP-binding protein RHOF. PLoS One. 2019;14(4): e0215746. doi:10.1371/journal.pone.0215746
24. Jiang Z, Yu T, Fan Z, Yang H, Lin X. Krüppel-like factor 7 is a marker of aggressive gastric cancer and poor prognosis. Cell Physiol Biochem. 2017;43(3):1090-1099. doi:10.1159/000481748
25. Raghavan PR, inventor. US patent 8,722,093. May 13, 2014.
26. Raghavan PR, inventor. US patent 9,006,292. April 14, 2015.
27. Raghavan PR. Metadichol®-induced expression of sirtuins 1-7 in somatic and cancer cells. Med Res Arch. 2024;12(6). doi:10.18103/mra.v12i6.5371
28. Raghavan PR. Metadichol-induced expression of toll receptor family members in peripheral blood mononuclear cells. Med Res Arch. 2024; 12(8). doi:10.18103/mra.v12i8.5610
29. Raghavan PR. Metadichol®: a nano lipid emulsion that expresses all 49 nuclear receptors in stem and somatic cells. Arch Clin Biomed Res. 2023;7:524-536. doi:10.26502/acbr.50170368
30. Raghavan PR. Metadichol, a natural ligand for the expression of Yamanaka reprogramming factors in human cardiac, fibroblast, and cancer cell lines. Med Res Arch. 2024;12(6). doi:10.18103/mra.v12i6
31. Raghavan PR. Metadichol®-induced expression of circadian clock transcription factors in human fibroblasts. Med Res Arch. 2024;12(6). doi:10.18103/mra.v12i6.5371
32. Raghavan PR. Metadichol-induced KLF expression in PBMC cells links SIRTs, NRs, TLRs, and circadian genes: a systems-wide biology approach. Preprints. 2025:2025020271. doi:10.20944/preprints202502.0271.v1
33. Tetreault MP, Wang ML, Yang Y, et al. Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice. Gastroenterology. 2010;139(6): 2124-2134.e9. doi:10.1053/j.gastro.2010.08.048
34. Tarapore RS, Yang Y, Katz JP. Restoring KLF5 in esophageal squamous cell cancer cells activates the JNK pathway leading to apoptosis and reduced cell survival. Neoplasia. 2013;15(5):472-480. doi:10.1593/neo.122126
35. Lahiri SK, Zhao J. Krüppel-like factor 8 emerges as an important regulator of cancer. Am J Transl Res. 2012;4(3):357-363.
36. McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev. 2010;90(4):1337-1381. doi:10.1152/physrev.00058.2009
37. Yang Y, Katz JP. Krüppel-like factors in the biology of cancer. In: Nagai RF, Friedman SL, Kasuga M, eds. The Biology of Krüppel-like Factors. Springer; 2009:67-82.
38. Tetreault MP, Yang Y, Katz J. Krüppel-like factors in cancer. Nat Rev Cancer. 2013;13:701-713. doi:10.1038/nrc3582
39. Zhang Y, Yao C, Ju Z, et al. Krüppel-like factors in tumors: key regulators and therapeutic avenues. Front Oncol. 2023;13:1080720. doi:10.3389/fonc.2023.1080720
40. Rascio F, Spadaccino F, Rocchetti MT, et al. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance. Cancers (Basel). 2021;13(16):3949. doi:10.3390/cancers13163949
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