Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

Abstract

The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

“…1c and 1d). Cyclin-dependent kinase inhibitor p21 WAF/Cip1 , also referred to as cdkn1a, has been known to be activated by p53 (reviewed in Kumar et al, 2006;Maddika et al, 2007) or induced by TGF-β through a p53-independent mechanism (Datto et al, 1995). Together, these results indicate lithium's inhibitory effects on Smad3/4-dependent TGF-β signaling.…”

“…Intravenous tPA has been used to treat acute stroke because of its thrombolytic activity and its ability to restore circulation to the brain (Hacke et al, 1995). Controversial results suggest that the tPA-plasmin system can be either protective or harmful in response to neurological insults (Tsirka , 2002;Maddika et al, 2007). For example, sufficient release of PAI-1 from astrocytes into the extracellular environments of neurons prevents neuronal apoptosis (Soeda et al, 2001;Docagne et al, 2002).…”

Caffeine Inhibits Cell Proliferation and Regulates PKA/GSK3β Pathways in U87MG Human Glioma Cells

“…Cell cycle progression from the G 0 /G 1 to the S phases is mainly controlled by two proteins, p21 and Rb (Maddika et al, 2007;Ohtani et al, 2004). The cyclin-dependent kinase (cdk) inhibitor, p21, negatively regulates cell cycle progression by inhibiting the activity of cyclin/cdk2 complexes and plays an important role in cell senescence and apoptosis (Kang et al, 2009;Lee et al, 2009).…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Although our understanding of the signaling and crosstalk mechanisms responsible for the phenomena of cell growth, survival, death and proliferation advances rapidly, it also poses new challenges for the development of in vivo assessment methods of matching accuracy (Kim, 2005;Maddika et al, 2007;Eisenberg-Lerner et al, 2009). In addition to measurements of cell death (Al-Ejeh et al, 2007, 2009Cohen et al, 2007;Kartachova et al, 2007), proliferation and senescence (SA-b-gal staining) can also be measured by noninvasive real-time live imaging.…”