Polyamines are well recognized for their critical role in supporting cell proliferation-a role that has been preclinically validated as a worthy anticancer target. During the past granting period, we have described the signaling, effectors and survival responses elicited by polyamine inhibitors or analogs in arrest-prone MALME-3M melanoma cells and in apoptosis-prone SK-MEL-28 cells. In the case of analogs, potent induction of the catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), emerged as the key initiator of metabolic and signaling events that culminate in apoptosis or cell cycle arrest. That linkage was confirmed by SSAT-targeted RNAi, making DENSPM the only polyamine analog having a defined mechanism of growth inhibition. In pursuit of downstream metabolic events, we have genomically identified and biochemically characterized (a) an analog-inducible spermine oxidase, (b) an analog-inducible polyamine oxidase, and (c) a second SSAT. Taken together, these various findings present converging opportunities for investigating how analog induction of polyamine catabolism relates to apoptosis and cell cycle arrest and for devising mechanism-based strategies for exploiting these findings towards a therapeutic advantage. The following Specific Aims pursue these significant new leads in the same two melanoma cells with the goal of determining how inducible polyamine catabolic systems mechanistically interface with recently defined pathways of cell cycle arrest and apoptosis.
Aim 1 will determine the relative contribution of new polyamine catabolic enzymes in analog-induced apoptosis of SK-MEL-28 cells;
Aim 2 will identify downstream signaling molecules linking polyamine catabolism to apoptosis in analog treated SK-MEL-28 cells;
Aim 3 will determine the relative contribution of p53 and new polyamine catabolic enzymes in analog-induced cell cycle arrest of MALME-3M cells;
Aim 4 will identify downstream signaling molecules linking polyamine catabolism to apoptosis in analog treated MALME-3M cells, and Aim 5 will validate the role of polyamine catabolic enzymes in mediating or contributing to DENSPM antitumor activity.
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