The anticancer effects of vitamin K

Alternative Medicine Review,  August, 2003  by Davis W. Lamson,  Steven M. Plaza

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Transcription Factors

The non-oxidative model of vitamin K action focuses on the modulation of transcription factors, which in turn induce cell cycle arrest and apoptosis. ROS, protein tyrosine kinases, and protein tyrosine phosphatases modulate transcription factors, which in turn induce the transcription of growth factors, inflammatory cytokines, and apoptotic controlling factors from proto-oncogenes. These proto-oncogene proteins, involved in the regulation and/or differentiation of cell growth, often have a protein kinase activity. Protein kinases phosphorylate proteins in response to intracellular and extracellular stimuli. They in turn act as the "on switch," turning on a number of enzymes and proteins. Phosphatases, acting as the "off switch," control the activation of protein kinases by dephosphorylating the various proteins and enzymes.

The expression of c-myc and c-fos proto-oncogenes are involved in the mechanism of vitamin K induced apoptosis, differentiation, and cell cycle arrest. The proto-oncogene myc (c-myc) codes for a nuclear protein transcription factor c-Myc (as part of a heterodimeric complex with Max protein) that activates other genes. (88) In the case of the oncogene c-myc, the complex is involved in transformation, immortalization, cell differentiation, and induction of apoptosis (Figure 6). (89)

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The proto-oncogene c-fos codes for a nuclear protein, which is involved in growth related transcriptional control. The c-fos and c-jun gene products are both components of the transcription complex AP-1. AP-1 is a nuclear transcription factor that regulates growth and tumor promotor stimuli. The c-Fos and c-Jun gene products dimerize in order to bind to the AP-1 recognition site. Jun has been associated with cellular transformation and activation of transcription.

C-myc proto-oncogene is best thought of as a modulator of cellular function, such as apoptosis, as it can promote both proliferation and apoptosis depending on its expression. (90,91) Mutation of the proto-oncogene to the c-myc oncogene can foster malignant transformation and increase cell proliferation. The addition of vitamin K (K1, K2, and K3) to malignant cell cultures has been found to result in induction of proto-oncogenes and an increase in the level of a number of proto-oncogene proteins, c-myc, c-jun, and c-fos. (14,92) Wu et al (14) found that 50 [micro]M of K3 transiently induced c-fos proto-oncogene expression in vitro in one hour, while c-myc proto-oncogene expression was increased for 1-9 hours after treatment with concomitant increase in c-Fos and c-Myc transcription factors. These changes were associated with cell cycle delay or arrest and apoptosis. K3 is the most potent stimulator, followed by K2 then K1. (17)

The proto-oncogene bcl-2 has been shown to protect against apoptosis. The addition of bcl-2 to cell cultures (2B4 and FL5.12) countered the cell death imposed by the oxidative burst from K3. Bcl-2 was not able to decrease the ROS produced by K3, as measured by cyanide-resistant oxygen consumption, yet it was able to inhibit dose-related killing of the cell lines from 50 [micro]M-200 [micro]M of K3. These results suggest that ROS, acting as second messengers, signal downstream transcription factors, such as nuclear factor-kappa B (NF-kB), Fos/Jun, and others that may be protected by the antioxidant-governing activities of Bcl-2. (93) The transcription factor NF-kB is involved in stress-induced FasL expression. Fas is one of the important death receptors in the tumor necrosis factor superfamily. The gene encoding the ligand for Fas, designated as FasL, activates Fas by trimerization of the receptor. Activation-induced cell death is commonly mediated by the Fas/FasL system, and menadione induces Fas as well as FasL expression. Capriccio et al (94) found that a functional Fas/ FasL system was needed in order to induce apoptosis. Experiments showed that mutant leukemia cell lines lacking a functional Fas ligand were resistant to FasL killing by menadione. It was also found that mice lacking functional FasL or expression of Fas were also resistant to the cytotoxic effects of K3.