chapter  5
36 Pages

Cancer Cell M etabolism , Cell C ycle, and Cell D eath (Apoptosis, Necrosis)

Also recent data strongly suggest the significance of cell cycle and its regula­ tors (cyclins, cyclin-dependent kinases (CD Ks), and their inhibitors), apoptosis and its inhibitors and their param ount significance for cancer therapy and devel­ opm ent of novel anticancer drugs (1-4). H ence, both cell cycle and apoptosis becam e potential targets for cancer treatm ent and design of new anticancer drugs. Since cancer cells differ from norm al cells in m any im portant characteris­ tics, including loss of differentiation, increased invasiveness and decreased drug sensitivity, and m ore recently the alterations in the critical regulatory proteins as a frequent defect in cancer cells. Thus these abnorm al m etabolic proteins, result­ ed from an enhanced "p roteo lysis" in cancer cells are p laying key regulatory roles in cell cycle, apoptosis, cell necrosis, and consequently a close interrelation betw een cancer cell m etabolism and fundam ental cell processes including cell cycle and apoptosis becam e the focus of several biochem ical, genetic and m olec­ ular studies, and the num ber of publications in this field dram atically increased in the last decade. Clearly, the balance o f protein concentrations, and the role of these "protein actives" is critical to the hom eostatic m echanism s of cancer cells (5 -7). A lthough, m ost o f the previous investigations indicated that the cell cycle is regulated m ainly by the w ell-tim ed production of regulatory proteins and their key role in controlling cell cycle, cell proliferation and tum or suppression by the n u cleocy top lasm ic tran sp ort and recen tly d iscovered in p ortin -a lp h a and

im portin-beta proteins w hich prom ote the transport of proteins into the nucleus as w ell as out of the nucleus back to the cytoplasm to prom ote new rounds of im port (or pendulin proteins) (5, 7). Recently a new protein term ed CAS (for cellular apoptosis susceptibility), a m am m alian m em ber of the im port in-beta pro­ teins w hich is m ay be im portant for translocation into the nucleus of som e com ­ ponent of the tum or necrosis factor (TNF) activated signal transduction pathway. Thus different im portin-beta proteins m ay carry different classes of proteins and RN As both in and out of the nucleus, and the loss of function of different fam ily m em bers could result in different cell phenotypes. For instance, loss of CAS func­ tion appears to render cells resistant to apoptosis, while loss of transport of APC (anaphase prom oting com plex) m ay enhance the tendency to undergo apoptosis (7, 8).