| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 105 === More than 95% chronic myeloid leukemia (CML) patients carry the constitutively activated tyrosine kinase, BCR-ABL fusion protein. Therefore, tyrosine kinase inhibitors (TKIs) are designed for CML treatment. However, some patients have no response to TKIs especially for those patients with relapsed or diagnosed at blast crisis (BC) phase. Thus, it is needed for developing alternative approaches for CML treatment. Cyclic AMP (cAMP) regulates cell proliferation via ribosomal protein S6 kinase 1 (S6K1). The expression of tumor suppressor gene, p53, is involved in the disease progression and affects drug resistance in CML. The purpose of our study is to investigate whether the relationship between cAMP, S6K1 and p53 in drug resistance in CML cells. We observed that increased level of cAMP conferred cisplatin resistance in CML cells. From the experiments of the activators of protein kinase A (PKA) and exchange protein directly by cAMP (EPAC), we observed that PKA is the effector on cAMP-induced cisplatin resistance. We also found that increased level in cAMP reduced the formation of pS6K1 and pRPS6. Furthermore, inhibition and knockdown of S6K1 lead to cisplatin resistance in CML cells. Next, we observed that S6K1 acts via DNA-PKcs, H2AX and PARP regulating cisplatin resistance. Last but not the least, p53 expression attenuates the effect of S6K1 on cisplatin resistance in CML cells. In conclusion, the level of cAMP should be considered when choosing chemotherapeutic drug such as cisplatin for CML treatment. More importantly, we suggest that p53 expression is crucial for choosing the inhibitor of S6K1 signaling pathway as the adjuvant agent with chemotherapeutic drug in CML treatment.
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