Targeting disease through novel pathways of apoptosis and autophagy

Abstract

Introduction: Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments.

Areas covered: Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented.

Expert opinion: The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.

Figure 1. Signaling pathways of apoptosis and autophagy during oxidative stress

Oxidative stress can lead to the activation of initiator caspases, such as caspase 8, which can directly activate caspase 3 and cleave BH3 domainonly protein Bid. The resultant truncated Bid (tBid) promotes the release of cytochrome c from mitochondria through Bax. Cytochrome c interacts with apoptotic protease-activating factor-1 (Apaf-1) resulting in the oligomerizaton of Apaf-1 and the subsequent activation of caspase 9. Activated caspase 9 can activate caspase 3 as well as caspase 1 leading to apoptotic DNA fragmentation and phosphatidylserine (PS) exposure. In response to oxidative stress, expression of the anti-apoptotic protein Bcl-2/Bcl-x_L is down-regulated. This process releases the autophagy-related protein Beclin 1 from inhibitory binding by Bcl-2/Bcl-x_L and initiates autophagic cell death. In addition, Bcl-2/Bcl-x_L also antagonizes Bax-mediated mitochondrial release of cytochrome c to prevent the induction of caspase activation and apoptosis.

Figure 2. Pathways of WISP1, PI3K, Akt, β-catenin and mTOR that control cell fate

WISP1 results in the activation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B). Following activation, Akt can phosphorylate glycogen synthase kinase-3β (GSK-3β). The phosphorylated (p) GSK-3β loses its ability to phosphorylate β-catenin, allowing β-catenin to enter into the nucleus and promoting gene transcription that fosters WISP1 expression and leads to ‘anti-apoptotic’ protein production. Activation of Akt also phosphorylates the pro-apoptotic protein Bad. This process releases Bcl-x_L from the binding to Bad to prevent Baxmediated mitochondrial (Mito) membrane depolarization, cytochrome c release and subsequent caspase activation. In addition, activation of the mammalian target of rapamycin (mTOR) is intimately involved in cell apoptosis and autophagy. Proline-rich Akt substrate 40 kDa (PRAS40) is one target of Akt phosphorylation. PRAS40 is an inhibitory protein of mTOR and its phosphorylation by Akt results in the loss of its ability to prevent mTOR activation.