New insights into vitamin K biology with relevance to cancer

Abstract

Phylloquinone (vitamin K1) and menaquinones (vitamin K2 family) are essential for post-translational γ-carboxylation of a small number of proteins, including clotting factors. These modified proteins have now been implicated in diverse physiological and pathological processes including cancer. Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies. Newly discovered functions of vitamin K in cancer cells include activation of the steroid and xenobiotic receptor (SXR) and regulation of oxidative stress, apoptosis, and autophagy. We provide an update of vitamin K biology, non-canonical mechanisms of vitamin K actions, the potential functions of vitamin K-dependent proteins in cancer, and observational trials on vitamin K intake and cancer.

Keywords: Gla proteins; cancer; menaquinone; phylloquinone; vitamin K.

Figure 1.. Forms and Function of Vitamin K.

A. Structure of vitamin K1 (Phylloquinone or PK) and vitamin K2 family (menaquinones or MK). B. The gamma-glutamyl carboxylase (GGCX) utilizes vitamin K1 or K2 hydroquinones to drive γ-carboxylation of glutamate (Glu) residues and generate γ-carboxyglutamate (Gla) residues in target proteins. The resulting vitamin K epoxides are sequentially reduced to hydroquinones by vitamin K epoxide reductases (VKOR, encoded by the VKORC1 and VKORC1L1 genes) and an as-yet-unknown vitamin K reductase (VKR). Figure created with BioRender.com.

Figure 2.. Mechanisms of induction of apoptosis and autophagy by MK4.

MK4 induces apoptosis through production of ROS which activates ERK, JNK/p38 MAPK, and initiates binding of MK4 to BAK. Activation of ERK results in up-regulation of BAX, decrease in mitochondrial membrane potential (MMP), and cytochrome c release. JNK/p38 MAPK activation results in down-regulation of BCL2. MK4 covalently bound to BAK induces decrease in MMP and cytochrome c release. The outcome of mitochondrial dysfunction and cytochrome c release is caspase activation which results in apoptosis. ROS production can be blocked by N-acetyl-cysteine (NAC) and alpha-tocopherol which can ultimately block MK4 mediated apoptosis. MK4 also induces metabolic stress by reducing ATP production and increasing lactate production which activates AMPK and in turn blocks MTORC1 (responsible for protein synthesis and proliferation) and initiates autophagy and formation of autophagosomes with up-regulation of LC3B-II. 3-Methyladenine (3MA) can block autophagosome formation. Arrows denote activation; blunt ended arrows denote inhibition. Figure created with BioRender.com.

Figure 3.. MK4 biosynthesis by UBIAD1 and activation of SXR.

UBIAD1 is the biosynthetic enzyme responsible for MK4 production from K vitamins (PK and MKs) and formation of cellular pools of MK4. The side chain of K vitamins is cleaved by an unknown enzyme to form menadione (Men) which is prenylated by UBIAD1 utilizing the isoprenoid geranylgeranyl pyrophosphate (GGpp) to produce MK4. UBIAD1 translocates from the ER to the Golgi when sterol synthesis is high, thus regulating sterol synthesis and maintaining isoprenoid synthesis. MK4 can bind and activate the transcription factor SXR and up-regulate expression of many genes including those involved in cholesterol catabolism and efflux, thus reducing cancer phenotype. Figure created with BioRender.com.