The role of p53-independent apoptotic pathways in tumorigenesis

Apoptosis is a critical process for the maintenance of cellular homeostasis and prevention of cancer. BCL-2 family proteins play a central role in the regulation of apoptosis and modulate death signaling through mitochondrial pathway.{09}The strong impact of the BCL-2 family on tumor development is well illustrated by findings with baby mouse kidney epithelial (BMK) cells immortalized by E1A and dominant negative p53 (p53DD). Immortalized BMK (iBMK) cells from mice deficient for both BAX and BAK, or that overexpress BCL-2, readily form tumors in nude mice, whereas those retaining functional BAX and/or BAK do not, suggesting that a p53-independent, but BAX and BAK-dependent apoptotic pathway is implicated in tumor suppression. Hence, understanding the molecular events regulating this p53-independent apoptotic pathway may provide insights into tumorigenesis and reveal novel targets for effective therapeutic approaches to cancer treatment. We show that in epithelial cells, ischemic conditions in the tumor microenvironment cause induction of the BH3-only protein PUMA, and BAX-and BAK-mediated apoptosis that suppresses tumorigenesis independent of the RB and p53 pathways. Blockade of this p53-independent apoptotic pathway by either loss-of-function of BAX and BAK or gain-of-function of BCL-2 in vivo does not merely extend viability, but also allows survival of genetically unstable cells which may further promote tumor development. Furthermore, determining the mechanism of apoptosis induction by the chemotherapeutic drug paclitaxel revealed that BH3-only protein BIM suppressed tumorigenesis and was required for paclitaxel responsiveness.{09}The targeting of BIM for degradation in proteasomes by the H-ras/MAPK pathway was the molecular basis for paclitaxel resistance in tumors with activating mutations in RAS, and paclitaxel responsiveness was restored by joint administration of the proteasome inhibitor Velcade. Thus rational combinatorial chemotherapy using proteasome inhibitors to enhance chemosensitivity to paclitaxel in tumors where the H-ras/MAPK pathway is activated may be therapeutically beneficial, implying that relating tumor genotype to effective treatment regimens is essential for successful therapeutic outcome. Finally, studying the enhanced tumorigenesis of tumor derived cell lines (TDCLs) after in vivo selection showed that multiple capabilities may be selected for and cooperate with each other during tumorigenesis, revealing the complexity of cancer development.