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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2018.1
- 수록면
- 1,023 - 1,038 (16page)
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Purpose Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. Materials and Methods We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivomodels of HCCs. Results HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. Conclusion The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.
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참고문헌 (30)
참고문헌 신청
Altekruse SF / 2009 / Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005 / J Clin Oncol 27:1485~1491
El-Serag HB / 2011 / Hepatocellular carcinoma / N Engl J Med 365:1118~1127
Villanueva A / 2008 / Pivotal role of mTOR signaling in hepatocellular carcinoma / Gastroenterology 135:1972~1983
Laplante M / 2012 / mTOR signaling in growth control and disease / Cell 149:274~293
Sparks CA / 2010 / Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy / Oncogene 29:3733~3744
El-Serag HB / 2011 / Hepatocellular carcinoma / N Engl J Med 365:1118~1127
Villanueva A / 2008 / Pivotal role of mTOR signaling in hepatocellular carcinoma / Gastroenterology 135:1972~1983
Laplante M / 2012 / mTOR signaling in growth control and disease / Cell 149:274~293
Sparks CA / 2010 / Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy / Oncogene 29:3733~3744
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