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논문 기본 정보
- 자료유형
- 학위논문
- 저자정보
- 발행연도
- 2015
- 저작권
- 서울대학교 논문은 저작권에 의해 보호받습니다.
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Pim kinases are highly conserved serine/threonine kinases that control proliferation and survival pathways in cancer cells. Different expression patterns of each Pim isoform (Pim-1, Pim-2 and Pim-3) have been observed in various types of human cancer including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three Pim kinase isoforms. In the present study, we used AZD1208 to demonstrate that inhibition of Pim kinase activity induces gastric cancer cell death. Treatment with AZD1208 alone down-regulated the expression of the Pim kinase substrates, but cell viability in short-term cell cultures was not observed. In long-term cultures, we observed significantly decreased cell viability and up-regulated expression of light chain 3B (LC3B), an autophagy marker, in a dose-dependent manner only in the AZD1208-sensitive cell line. This finding suggested that the cytotoxic effect of AZD1208 was achieved through autophagy and not apoptosis. Moreover, we found that ataxia telangiectasia mutated (ATM) and checkpoint kinase (CHK2), two critical components of the DNA repair pathway, were activated in an AZD1208-resistant cell line. We also confirmed that a combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. Taken together, our data demonstrated that treatment with AZD1208 alone induced considerable cell death through autophagy. Additionally, a combination of Pim and Akt inhibitors had a strongly synergistic effect in human gastric cancer cell lines.
목차
TABLE OF CONTENTSABSTRACT ---------------------------------------------------- iTABLE OF CONTENTS ----------------------------------iiiLIST OF TABLES ------------------------------------------ ivLIST OF FIGURES ----------------------------------------- vINTRODUCTION ------------------------------------------- 1PURPOSE OF THIS STUDY---------------------------- 4MATERIALS AND METHODS ----------------------- 5RESULTS ------------------------------------------------------ 12DISCUSSION ------------------------------------------------ 36REFERENCES ---------------------------------------------- 39ABSTRACT IN KOREAN ------------------------------ 44LIST OF TABLESTABLE 1. Sequences of the primers for PCR and real-time PCR analyses. ---------------------------------------------------- 8TABLE 2. Effects of AZD1208 on the inhibition of human gastric cancer cell growth. ------------------------------------- 14TABLE 3. Genetic background of gastric cancer cell lines.--------------------------------------------------------------------- 21TABLE 4. Combined effects of AZD1208 and an Akt inhibitor. --------------------------------------------------------- 35LIST OF FIGURESFigure1. AZD1208 showed minimal cytotoxic effect in gastric cancer cell lines. ---------------------------------------- 13Figure2. AZD1208 induces growth inhibition of Gastric cancer cell lines. ------------------------------------------------- 14Figure3. Different expression levels of Pim kinases in gastric cancer cell lines. ------------------------------------------------- 18Figure4. AZD1208 affects downstream molecules of Pim kinase. ------------------------------------------------------------- 24Figure5. Apoptosis is not associated with cytotoxic effect of AZD1208. -------------------------------------------------------- 25Figure6. AZD1208 induces cell death through stimulate autophagy. ------------------------------------------------------- 28Figure7. DNA damage repair pathway is associated with resistance to AZD1208. ---------------------------------------- 33
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