However, Van Poznak et al. and Zhang et al. sug gested that gossypol induced cell cycle arrest is associated with alterations of p21, cyclin D1, and p53 and showed that p21 is the first target of gossypol to inhibit cell growth in vivo. Our data indicated that ApoG2 induced massive cells arrest at S phase of the cell cycle not only in ApoG2 sensitive NPC cells but also in ApoG2 phase 3 insensitive HONE 1 cells. Results of signaling pathway anal ysis showed that downregulation of c Myc protein Inhibitors,Modulators,Libraries expres sion was the major upstream event in ApoG2 induced cell cycle arrest in NPC cells. Basically, the effect of c Myc on cell cycle is to drive quiescent cells into the cell cycle, and shortening G1 and promoting S phase entry thereby. The down regulation of c Myc should cause a Inhibitors,Modulators,Libraries preferential G1 S arrest rather than S arrest.

However, in NPC cells, although p53 was highly expressed and its expression was never downregulated by ApoG2 in Inhibitors,Modulators,Libraries this study, p53 was mutated and functionally impaired by Epstein Barr virus nuclear antigen 5 and deltaN p63 in NPC cells. In this scenario of malfunction of G1 S checkpoint p53, c Myc was a main factor accounting for ApoG2 induced S phase arrest. P21 and cyclins were fol lowed by downregulation of c Myc expression. c Myc is not only a central regulator of cell proliferation but also induces cells to undergo apoptosis, unless spe cific signals provided by oncogenes block the apoptosis pathway. Notably, NPC cells consistently harbor EBV DNA and express EBV proteins, LMP1 and BARF1. these proteins stimulate oncogenic antiapoptotic Inhibitors,Modulators,Libraries Bcl 2 proteins to protect host cancer cells from apoptosis.

ApoG2 is a potent inhibitor of antiapoptotic Bcl 2 pro teins and its treatment could remove the protective effect of Bcl 2 proteins and facilitate apoptosis. In this case, downregulation of c Myc expression by ApoG2 on one hand could let cells away from c Myc induced apoptosis and on other hand led to cell cycle arrest. However, Inhibitors,Modulators,Libraries by inhibiting Bcl 2 proteins, ApoG2 still helped release pro apoptotic proteins, such as Bax and Bak, and irreversibly damaged mitochondria and induced cell apoptotic. Gossypol is clinically used in China to treat adenomyosis and hysteromyoma because of its ability to inhibit estro gen and progesterone by competitively binding to the estrogen receptor and progesterone receptor. c Myc is a well established target of estrogen action and plays a role in controlling cell cycle progression. Anti estrogen treatment is reported to be able to cause an acute decrease in c Myc expression, a subsequent selleck catalog decline in cyclin D1 expression, and, ultimately, inhibition of DNA synthesis and arrest of cells in a quiescent state.