Cell survival and apoptosis signaling as therapeutic target for cancer: marine bioactive compounds

Abstract

Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow.

Figure 1

Scheme of PI3K/AKT mediated antiapoptotic regulations at the mitochondria. AKT phosphorylated by PI3K activation. AKT phosphorylates and inhibits Bax and Bad (both are proapoptotic protein). AKT activates mTOR, which in turn phosphorylates and activates antiapoptotic protein MCL-1 (induced myeloid leukemia cell differentiation protein). AKT also activates NF-κB (nuclear factor kappa B), thus resulting in transcription of pro-survival gene Bcl-XL (B-cell lymphoma-extra large). AKT phosphorylates and inhibits proapoptotic protein Bax. NF-κB phosphorylates the X-linked inhibitor of apoptosis protein (XIAP), then binds to and inhibits caspases. Bim (Bcl-2 interacting mediator of cell death) and Noxa are the only proapoptotic BH-3 protein inhibited by FOXO3 protein (Forkhead box O3), phosphorylated by AKT in the PI3K signaling pathway.

Figure 2

Scheme of survival signaling cascade by receptor tyrosine kinases via PI3K/AKT mediated survival. The binding of a ligand (Growth Factor) to its receptor triggers intrinsic tyrosine kinase phosphorylation, subsequently activating IRS and PI3K. Activated PI3K generates phosphatidylinositol-3,4,5-triphosphate, which recruits phosphatidylinositol-dependent kinase (PDK) and AKT serine/threonine kinase at the plasma membrane, resulting in phosphorylation of AKT. After phosphorylation, activated AKT inactivates other apoptogenic factors, Bad (a pro-apoptotic protein, which in its non-phosphorylated state, promotes apoptosis) and caspase 9. AKT also activates mTOR by phosphorylation. The transcription factor NF-κB can lead to transactivation of a wide range of antiapoptotic NF-κB target genes (e.g., Bcl-XL and Bcl-2). AKT also phosphorylates MDM2 (murine double minute protein), which in turn inhibits p53 action. On the other hand, cell survival and proliferative signals are mediated by the Ras/Raf pathway (Figure 2). Receptor tyrosine kinase phosphorylation also activates the GRB/SOS2 (Growth factor receptor-bound protein 2/Son of Sevenless, adaptor proteins), which in turn activates Ras (Rous sarcoma protein). Then, Ras activates Raf-1(Receptor activated factor-1) kinase, which subsequently activates the MEK and ERK, thereby regulating the survival, proliferation, migration and invasion of cancer.

Figure 3

Pathway of apoptosis. Extrinsic cell death pathway is mediated by a TNF receptor superfamily, called the death receptors. Receptor-mediated cell death is initiated by the recruitment of adapter proteins, like FADD (Fas associated death domain), via the DD (death domain), which then bind to the death effector domain-containing caspase-8 or -10. Formation of this DISC (death inducing signaling complex) results in the activation of caspase-8/10, which then directly cleaves and activates the executioner caspase-3. Mitochondrial or intrinsic pathway, proapoptotic Bcl-2 family members, Bax and Bak, translocate to the mitochondria. The BH3-only protein Bid activates Bax and Bak oligomerisation form an oligomeric pore in the outer mitochondrial membrane. This results in the release of cytochrome c and other pro-apoptotic factors from the mitochondria to the cytosol. Cytochrome c triggers the assembly of the apoptosome (Apaf-1, caspase-9 and also the nucleotide adenosine tri phosphate (ATP) as a third component, binds and forms apoptosome). Subsequently, apoptosome activates caspase-3 and cell death. IAP (inhibitor of apoptosis protein) binds directly to caspases and inhibits their enzymatic activity. The inhibitory function of IAPs is controlled by the SMAC (Second mitochondria-derived activator of caspases).

Figure 4

Interaction of marine compounds on survival and apoptotic signaling molecules. Regulation of this pathway with marine compounds; arrow indicates activation and blocked arrow indicates inhibition of the molecules.