The individualization of cancer therapy: the unexpected role of p53.

Abstract

Our laboratory discovered that p53 can regulate the sensitivity to cancer therapies by affecting three critical aspects of cancer pharmacology: 1). The expression of drug targets; 2). the access of drugs to intracellular targets; and the response to DNA damage. We review the effects of p53 on antimicrotubule drugs through transcriptional regulation of MAP4 and stathmin (Oncoprotein 18). These two p53-regulated proteins control microtubule dynamics, regulate the sensitivity to taxanes and vinca alkaloids by changing the polymerization dynamics of tubulin and affecting the binding of drugs to microtubules. We found that overexpression of MAP4 increased microtubule polymerization and increased taxane binding and sensitivity. Overexpression of stathmin, a microtubule destabilizer, virtually abolished cellular taxane binding and increased resistance by over 1000-fold. Yet, despite an increased binding of vinca alkaloids to stathmin transfectants, we did not observe increased drug sensitivity. This was explained, at least in part, by a delay in G2/M transit. We also discovered that p53 could regulate the expression of multidrug resistance protein-1 (MRP1), a member of the ABC family of transporters that mediates the sensitivity to vinca alkaloids and anthracyclines. We found that as prostate cancer progressed from low stage/low grade to high stage/high grade there was an increased expression of both MRP1 and staining for p53, a surrogate for p53 mutations. We went on to show that p53 regulated the expression of MRP1 and that this produced resistance to doxorubicin and vinblastine. We further demonstrated that MRP1 overexpression blocked the accumulation of flutamide and hydroxy-flutamide (the active metabolite) without affecting transport of dihydrotesterone, thereby blocking access of the anti-androgen but not the androgen to intracellular androgen receptors. Finally, we reviewed the effects of DNA damage on p53 expression and MAP4 repression as a means to increase the effectiveness of breast cancer treatment. These data demonstrated the possibility of individualizing treatment based on p53 status.