Tocotrienols Modulate a Life or Death Decision in Cancers

Abstract

Malignancy often arises from sophisticated defects in the intricate molecular mechanisms of cells, rendering a complicated molecular ground to effectively target cancers. Resistance toward cell death and enhancement of cell survival are the common adaptations in cancer due to its infinite proliferative capacity. Existing cancer treatment strategies that target a single molecular pathway or cancer hallmark fail to fully resolve the problem. Hence, multitargeted anticancer agents that can concurrently target cell death and survival pathways are seen as a promising alternative to treat cancer. Tocotrienols, a minor constituent of the vitamin E family that have previously been reported to induce various cell death mechanisms and target several key survival pathways, could be an effective anticancer agent. This review puts forward the potential application of tocotrienols as an anticancer treatment from a perspective of influencing the life or death decision of cancer cells. The cell death mechanisms elicited by tocotrienols, particularly apoptosis and autophagy, are highlighted. The influences of several cell survival signaling pathways in shaping cancer cell death, particularly NF-κB, PI3K/Akt, MAPK, and Wnt, are also reviewed. This review may stimulate further mechanistic researches and foster clinical applications of tocotrienols via rational drug designs.

Keywords: apoptosis; autophagy; cancer; cell death; cell survival; tocotrienols.

Figure 1

Extrinsic and intrinsic pathways of apoptosis. The extrinsic pathway begins outside of a cell and involves the binding of extracellular death ligands to their respective transmembrane death receptors. The activation of tumor necrosis factor (TNF) receptor superfamily, such as first apoptosis signal (Fas), takes place, leading to activation of caspase-8 (initiator caspase) and recruitment of the Fas-associated protein with death domain (FADD) adapter molecule. It transduces a downstream signaling cascade to the effector caspase (caspase-8), leading to the proteolytic activation of caspase-3. In fact, the extrinsic pathway can cause amplification of cascade via intrinsic mitochondrial pathway whereby caspase-8 cleaves Bid to promote mitochondrial outer membrane permeabilization (MOMP) [32]. The intrinsic pathway is initiated by internal stimuli, such as genetic damage, growth factor deprivation, hypoxia, oxidative stress, and flux of calcium ions (Ca²⁺) [33]. The stimuli then perceive cell death signals via the mitochondrion, which represents the metabolic status of a cell. The MOMP is often regarded as the primary step required for activation of caspases. Proapoptotic and antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins are involved in regulating the permeability of outer mitochondrial membrane [34,35]. Upon apoptotic stimulus, MOMP takes place, leading to the release of cytochrome c from the intermembrane space. In the cytoplasm, cytochrome c engages apoptotic protease activating factor 1 (Apaf-1) and eventually leads to the activation of caspase-9 (initiator caspase). Following that, caspase-9 activates executioner caspases, such as caspase-3, -6, and -7, which subsequently cause the downstream biochemical events, leading to apoptosis [36].

Figure 2

The process of autophagy. During autophagy, phagophore (cup-shaped, double-membrane sac) emerges in cytoplasm, driven by unc-51-like kinase 1 (ULK1) complex and vacuolar protein sorting (Vps) 34 complex. The expansion of phagophore is facilitated by Atg5–12/Atg16L complex to uptake cargos from the cytoplasm into a double-membrane autophagosome. The loaded autophagosome then fuses with lysosome to allow the degradation of cargo by lysosomal proteases, while microtubule-associated protein light chain 3 (LC3-I) will be recycled back to cytosol. The endogenous LC3-I, present in the cytoplasm, is processed to LC3-II and bound to the autophagosome during autophagy. Therefore, the ratio of LC3-I (water soluble) and LC3-II (lipidated) is often used as a marker to assess autophagy. Then, the lysosomal permeases and transporters export amino acids and other by-products of degradation back to the cytoplasm, where they can be reused for building macromolecules and for metabolism [37]. Abbreviations: Atg, autophagy-related protein; FIP200, focal adhesion kinase family interacting protein of 200 kDa.

Figure 3

Proposed actions of tocotrienols (T3) in inducing mitochondrial pathway of apoptosis. A: direct displacement of Bcl-2 molecule by acting as a BH3 mimetic; B: transcriptional regulation of Bax gene expression; C: inhibition of IAP family; D: induction of caspase-independent apoptotic pathway after mitochondrial damage. Abbreviations: Apaf-1, apoptotic protease activating factor 1; Bcl-2, B-cell lymphoma 2; Cas-, caspase-; MOMP, mitochondrial outer membrane permeabilization; IAP, inhibitor of apoptosis protein; PARP, poly(ADP-ribose) polymerase; ROS, reactive oxidative species; AIF, apoptosis inducing factor; HtrA, high temperature requirement A; EndoG, endonuclease G. “?” indicates more investigations are required.

Figure 4

Overview of tocotrienols-induced ER-stress-mediated apoptosis. Tocotrienols interact with unknown receptor on cell surface to trigger ER stress. BiP dissociates from unfolded protein response (UPR) sensors (i.e., PERK, IRE1, and ATF6) to trigger the respective signaling pathways, leading to apoptosis. Abbreviations: BiP or GRP78, glucose-regulated protein; CHOP, CCAAT-enhancer-binding protein homologous protein; PERK, PKR-like ER-localized eIF2α kinase; IRE1, inositol-requiring enzyme 1; ATF, activating transcription factor; eIF2-α, eukaryotic initiation factor 2 alpha; Cas-, caspase-; PARP, poly(ADP-ribose) polymerase; sXBP1, spliced X-box binding protein 1, TRB3, tribbles 3. “?” indicates more investigations are required.

Figure 5

Schematic representation of potential interactions between tocotrienols-induced apoptosis and autophagy. Tocotrienols bind to Bcl-2 protein to displace proapoptotic protein (i.e., Bax) and proautophagic protein (Beclin-1) to initiate apoptosis and autophagy, respectively. Bax initiates MOMP to induce apoptosis, leading to generation of ROS, which serves as a second messenger to trigger the expression of autophagy-related protein (Atg). Tocotrienols upregulate de novo synthesis of ceramides, which can activate JNK signaling by phosphorylating Bcl-2 family proteins and induce Ca²⁺ release by ER stress, eventually resulting in apoptosis and autophagy. “?” indicates more investigations are required.

Figure 6

Tocotrienols suppress cell survival signaling pathways in cancers.