Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Effect of Proapoptotic Bcl-2 on Naringenin-induced Apoptosis in Human Leukemia U937 Cells

Naringenin에 의한 인체혈구암세포의 apoptosis 유발에 미치는 pro-apoptotic Bcl-2의 영향

  • Park, Cheol (Department of Molecular Biology, College of Natural Sciences, Dongeui University) ;
  • Jin, Cheng-Yun (School of Pharmaceutical Science, Zhengzhou University) ;
  • Choi, Tae Hyun (Department of Ophthalmic Optics, Daegu Technical University) ;
  • Hong, Su Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine) ;
  • Choi, Yung Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine)
  • 박철 (동의대학교 자연과학대학 분자생물학과) ;
  • ;
  • 최태현 (대구공업대학 안경광학과) ;
  • 홍수현 (동의대학교 한의과대학 생화학교실) ;
  • 최영현 (동의대학교 한의과대학 생화학교실)
  • Received : 2013.08.15
  • Accepted : 2013.09.17
  • Published : 2013.09.30
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Abstract

Naringenin, a naturally occurring citrus flavonone, is a potentially valuable candidate for cancer chemotherapy. However, the cellular and molecular mechanisms responsible for its anticancer activity are largely unknown. In the present study, we attempted to elucidate the mechanisms responsible for naringenin-induced apoptosis in human leukemic U937 cells. We found that naringenin markedly inhibited the growth of U937 cells by decreasing cell proliferation and inducing apoptosis, which was associated with the activation of caspases. A pan-caspase inhibitor, z-VAD-fmk, significantly inhibited naringenin-induced U937 cell apoptosis, indicating that caspases are key regulators of apoptosis in response to naringenin in U937 cells. Although the levels of antiapoptotic Bcl-2 and proapoptotic Bax proteins remained unchanged in naringenin-treated U937 cells, Bcl-2 overexpression attenuated naringenin-induced apoptosis. Furthermore, combined treatment with naringenin and HA14-1, a small-molecule Bcl-2 inhibitor, effectively increased the apoptosis through enhancement of XIAP down-regulation, Bid cleavage, and caspase activation, suggesting that the synergistic effect was at least partially mediated through the death receptor-mediated apoptosis pathway.

감귤류에 많이 함유되어 있는 naringenin은 항암화학요법제로서 중요한 가능성을 가지고 있으나 항암활성에 대한 분자생물학적 기전에 대해서는 명확히 밝혀져 있지 않다. 본 연구에서는 인체 혈구암세포인 U937 세포에서 naringenin이 유발하는 항암효과 및 항암기전을 조사하였다. Naringenin 처리에 의한 U937 세포의 증식억제는 apoptosis 유발과 연관성이 있었으며, 이러한 현상은 caspases 활성화와 밀접한 관련이 있었다. 그러나 pan-caspase inhibitor인 z-VAD-fmk의 선처리에 의하여 U937 세포에서 naringenin이 유발하는 apoptosis가 억제되는 것으로 나타났으므로 caspases가 apoptosis 유발의 중요한 조절자라는 것을 알 수 있었다. 또한 U937 세포에 naringenin을 처리하였을 경우 pro-apoptotic Bcl-2 및 anti-apoptotic Bax의 발현에는 아무런 변화가 나타나지는 않았지만 Bcl-2가 과발현된 U937/Bcl-2 세포에서 naringenin에 의한 apoptosis가 억제되었다. 하지만 small-molecule Bcl-2 inhibitor인 HA14-1 및 naringenin을 같이 처리하였을 경우에는 XIAP 발현감소, Bid 단편화 및 caspase-3 활성화를 통하여 다시 apoptosis가 유발되었다. 따라서 HA14-1 및 naringenin에 의한 apoptosis 상승효과는 death receptor-mediated apoptosis pathway를 경유한다는 것을 제시하는 결과이다.

Keywords

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