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CCB Research Forum - Albert Girotti, PhD, "Nitric Oxide-dependent Pro-survival and Pro-growth Signaling in Cancer Cells Subjected to a PDT-like Oxidative Challenge" - Jan. 16

Albert Girotti, PhD Professor Department of Biochemistry Medical College of Wisconsin Abstract: Many tumors exploit nitric oxide (NO) as an anti-apoptotic/pro-survival effector molecule. We recently discovered that two human breast cancer cell lines rapidly upregulated inducible nitric oxide synthase (iNOS) after being subjected to photodynamic stress sensitized by 5-aminolevulinic acid (ALA)-generated protoporphyrin IX in mitochondria. Apoptotic cell photokilling was strongly enhanced by iNOS inhibition, iNOS knockdown, or NO scavenging, indicating that iNOS/NO was acting cytoprotectively. Key signaling events associated with this response have been identified in human breast cancer COH-BR1 cells. Immunocytochemistry and Western analysis revealed a cytosol-to-nucleus translocation of transcription factor NF-κB in photostressed cells. Bay 11-7082, an NF-κB activation inhibitor, suppressed translocation and iNOS induction while stimulating apoptosis. This suggests that NF-κB played a key role in iNOS transcriptional activation. Wortmannin, a PI3K inhibitor, stimulated photostress-induced apoptosis while suppressing Akt phosphorylation, NF-κB activation, and iNOS induction, thus implicating Akt activation in the latter. In other aspects of cytoprotective signaling, iNOS inhibition or knockdown revealed that activation of pro-apoptotic JNK and p38 MAPK was suppressed by NO, possibly via S-nitrosation. However, possible activation of protein kinase G by cGMP from NO-stimulated guanylyl cyclase was ruled out. We also showed that iNOS-knockdown increased p53 expression under photostress but negated survivin induction, consistent with pro-apoptotic p53 being negatively regulated by NO and anti-apoptotic survivin being positively regulated. More recent studies revealed that ALA/light-stressed prostate cancer PC-3 cells also upregulate iNOS and NO as a cytoprotective strategy. Moreover, cells surviving photostress exhibited a striking NO-dependent growth spurt with a large increase in cell cycle S-phase occupancy. Our studies suggest that iNOS/NO induction may be a common response of tumor cells to PDT stress. If so, this could have a serious negative impact on treatment efficacy unless dealt with by rational interventions, e.g. use of appropriate iNOS inhibitors. (Supported by NIH grant CA70823 and a WBCS/MCW Cancer Center grant)