Akt, P53 And Mdm2 Mutual Adjustment Of The Significance Of In Vitro Anticancer Drug Research

The p53 tumorsuppressor protein and the Akt/PKB kinase play important roles in the transduction of proapoptotic and anti-apoptotic signals, respectively. We provide evidence that conflicting signals transduced by Akt and p53 are integrated via negative feedback between the two pathways. We used 3 different cell lines derived from K-ras latent mice lung tumors, which also have different status of p53 to study two platinum family members, classic one-cisplatin and a new star-Jm216. The invention of JM216 is because of the rising drug resistance to cisplatin, although Jm216 has been widely used , its mechanism still remains unknown. We found that the sensitivity of the two cell lines harboring wtp53 towards either cisplatin or JM216 depends on the counteraction between Akt and p53. p53 can repress the activation of Akt after drug treatment, while under physiological conditions it can induce Akt phosphorylation. Akt also can increase the degradation of p53 via stabilizing Mdm2. For JM216 induced cell death, p53 is less important than its role in cisplatin induced apoptosis. Moreover, Akt, Mdm2 and Bcl-2 are all involved in Jm216 triggered apoptosis. We also analyzed some late stage lung tumor samples from k-ras latent mice. We found that in most of them, if not all, p53 was deleted. This study provide some clues that the effect of anticancer drug treatment is cell type or tissue specific, for clinical treatment, it's dependent on individual's genetic background as well as the tumor genetic background.