Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy.
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 G1-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.
Maddika
Subbareddy
S
Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada.
Ande
Sudharsana Rao
SR
Panigrahi
Soumya
S
Paranjothy
Ted
T
Weglarczyk
Kazimierz
K
Zuse
Anne
A
Eshraghi
Mehdi
M
Manda
Kamala D
KD
Wiechec
Emilia
E
Los
Marek
M
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D016213:Cyclins / Q000502:physiology*; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D018844:Cyclin-Dependent Kinases