The individualization of cancer therapy: the unexpected role of p53.
The individualization of cancer therapy: the unexpected role of p53.
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发表时间：
2006
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通讯作者：
W. Hait;Jin-Ming Yang
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作者：
W. Hait;Jin-Ming Yang
我们的实验室发现，P53可以通过影响癌症药理学的三个关键方面来调节癌症治疗的敏感性：1)。药物靶点的表达；2)。药物对细胞内靶点的接触；以及对DNA损伤的反应。我们通过对MAP4和stathmin(癌蛋白18)的转录调控来综述P53在抗微管药物中的作用。这两个受P53调控的蛋白通过改变微管蛋白的聚合动力学，影响药物与微管的结合，控制微管的动力学，调节对紫杉烷和长春花碱的敏感性。我们发现，MAP4的过表达增加了微管聚合，增加了紫杉烷的结合和敏感性。微管失稳剂stathmin的过表达几乎取消了细胞内紫杉烷的结合，并使耐药性增加了1000倍以上。然而，尽管长春花碱与stathmin转染体的结合增加，我们并没有观察到药物敏感性的增加。这至少在一定程度上是由于G2/M过渡的延迟。我们还发现，p53可以调节多药耐药蛋白-1(MRP1)的表达，MRP1是ABC转运蛋白家族的成员，介导长春花碱和蒽环类药物的敏感性。我们发现，随着前列腺癌从低阶段/低级别进展到高阶段/高级别，MRP1的表达和P53的染色都增加了，P53突变的替代物。我们进一步证明，P53调节MRP1的表达，并产生对阿霉素和长春新碱的耐药性。我们进一步证明，MRP1的过表达阻止了氟他胺和羟基氟他胺(活性代谢物)的积累，而不影响双氢睾酮的转运，从而阻止了抗雄激素而不是雄激素对细胞内雄激素受体的访问。最后，我们综述了DNA损伤对P53表达和MAP4抑制的影响，以期作为提高乳腺癌治疗效果的手段。这些数据证明了基于P53状态进行个体化治疗的可能性。
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.