Journal of Cellular Biochemistry 88:128–137 (2003) Paradoxical Role of Apoptosis in Tumor Progression Katerina V. Gurova and Andrei V. Gudkov* Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio Abstract Tumors frequently acquire resistance to apoptosis that is expected to contribute to malignant phenotype and reduce sensitivity to treatment. In fact, inactivation of p53 tumor suppressor gene resulting in suppression of apoptosis serves as a negative prognostic marker. Surprisingly, expression of a strong anti-apoptotic protein Bcl-2, another mechanism to avoid apoptosis, was found to be associated with a favorable prognosis. This paradoxical anti-progressor function of Bcl-2 has been explained in literature based on the negative effect of Bcl-2 on cell proliferation. Here, by analyzing accumulated experimental and clinical data, we provide evidence supporting another hypothesis that defines apoptosis as an accelerator of tumor progression. The mechanism of anti-progressor function of Bcl-2 is based on creation of tumors that maintain control of genomic stability by eliminating selective advantages for the cells that acquire resistance to apoptosis through loss of p53. Thus, inhibition of apoptosis does not lead to loss of genomic stability and creates tumor environment that no longer supports further tumor progression and inhibitors of apoptosis can be considered as factors suppressing tumor progression. J. Cell. Biochem. 88: 128 – 137, 2003. ß 2002 Wiley-Liss, Inc. Key words: apoptosis; tumor progression; genomic stability; p53; Bcl-2 Defects in apoptotic signaling pathways are common in cancer cells [Evan and Vousden, 2001; Zornig et al., 2001 and references therein]. Inhibition of programmed cell death seems to be important for tumor initiation since apoptosis is thought to be involved in the pro- cess of eliminating cells with damaged DNA and cells with anomalies in cell cycle regulation (i.e., cells of high risk of malignant transfor- mation). Moreover, impaired apoptosis may enhance tumor progression and promote met- astasis by enabling tumor cells survival in circulation and in abnormal cellular micro- environment. Furthermore, inactivation of apop- totic response may increase cancer cell resistance to various forms of therapy [Johnstone et al., 2002, review]. Several oncogenes have been defined among genes encoding negative regulators of apoptosis (prototype is Bcl-2). On the other hand, there are multiple examples of tumor suppressor genes among pro-apoptotic genes (prototype is p53). This suggests that a loss of apoptosis may be the most important characteristic of malig- nant cell phenotype presumably associated with an unfavorable prognosis for cancer patients. Surprisingly, the analysis of the results of numerous clinical studies that estimates the prognostic value of various tumor markers indicates that such schematics are frequently oversimplified. Bcl-2 AS A FAVORABLE PROGNOSTIC MARKER: CLINICAL DATA The mechanism regulating the escape of tumor cells from apoptosis can be divided into two categories: (i) inactivation of sensors of apoptotic stimuli (such as inactivation of p53, the major mediator of different types of stress) or certain elements of apoptotic machinery (i.e., inactivation of caspases) and (ii) upregulation of anti-apoptotic factors (such as overexpres- sion of Bcl-2, or activation of Akt). Although, both mechanisms are known to contribute to the resistance of apoptosis in many tumors, the analysis of clinical data shows a remarkable difference between them in terms of their asso- ciation with positive or negative prognosis of the disease. Inactivation of p53 (and elimination of ß 2002 Wiley-Liss, Inc. Grant sponsor: NCI; Grant numbers: CA60730, CA88071, CA75179. *Correspondence to: Andrei V. Gudkov, Department of Molecular Biology/NC20, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleve- land, OH 44195. E-mail: gudkov@ccf.org Received 11 September 2002; Accepted 12 September 2002 DOI 10.1002/jcb.10382