Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Cytotoxic Mechanism of Docosahexaenoic Acid in Human Oral Cancer Cells

인체 구강암 세포주에서 Docosahexaenoic acid에 의한 세포독성 기전

  • Hong, Tae-Hwa (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Kim, Hoon (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Shin, Soyeon (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Jing, Kaipeng (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Jeong, Soyeon (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Lim, Hyun (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Yun, Donghyuk (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Jeong, Ki-Eun (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Lee, Myung-Ryul (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Park, Jong-Il (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Kweon, Gi-Ryang (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Park, Seung Kiel (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Hwang, Byung-Doo (Department of Biochemisty, College of Medicine, Chungnam National University) ;
  • Lim, Kyu (Department of Biochemisty, College of Medicine, Chungnam National University)
  • 홍태화 (충남대학교 의학전문대학원 생화학교실) ;
  • 김훈 (충남대학교 의학전문대학원 생화학교실) ;
  • 신소연 (충남대학교 의학전문대학원 생화학교실) ;
  • ;
  • 정소연 (충남대학교 의학전문대학원 생화학교실) ;
  • 임현 (충남대학교 의학전문대학원 생화학교실) ;
  • 윤동혁 (충남대학교 의학전문대학원 생화학교실) ;
  • 정기은 (충남대학교 의학전문대학원 생화학교실) ;
  • 이명렬 (충남대학교 의학전문대학원 생화학교실) ;
  • 박종일 (충남대학교 의학전문대학원 생화학교실) ;
  • 권기량 (충남대학교 의학전문대학원 생화학교실) ;
  • 박승길 (충남대학교 의학전문대학원 생화학교실) ;
  • 황병두 (충남대학교 의학전문대학원 생화학교실) ;
  • 임규 (충남대학교 의학전문대학원 생화학교실)
  • Received : 2013.02.19
  • Accepted : 2013.05.21
  • Published : 2013.05.30
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Abstract

In the United States, about 40,000 new cases of oral cancer are diagnosed each year and nearly 7,800 patients died from it in 2012. Omega-3 polyunsaturated fatty acids have been found to have anticancer effects in a variety of cancer cell lines and animal models, but their effect in oral cancer remains unclear. This study was designed to examine the effect of docosahexaenoic acid (DHA, a kind of omega-3 fatty acid) on oral cancer cells and the molecular mechanism of its action. We found that exposure of squamous cell carcinoma-4 (SCC-4) and squamous cell carcinoma-9 (SCC-9) human oral cancer cells to DHA induced growth inhibition in a dose- and time-dependent manner. Meanwhile, in addition to the elevated levels of apoptotic markers, such as cleaved PARP, subG1 portion and TUNEL-positive nuclei, DHA led to autophagic vesicle formation and an increase in autophagic flux, indicating the involvement of both apoptosis and autophagy in the inhibitory effects of DHA on oral cancer cells. Further experiments revealed that the apoptosis and autophagy induced by DHA were linked to inhibition of mammalian target of rapamycin (mTOR) signaling by AKT inhibition and AMP-activated protein kinase (AMPK) activation in SCC-9 cells. Together, our results suggest that DHA induces apoptosis- and autophagy-associated cell death through the AMPK/AKT/mTOR signaling pathway in oral cancer cells. Thus, utilization of omega-3 fatty acids may represent a promising therapeutic approach for chemoprevention and treatment of human oral cancer.

오메가-3 지방산은 많은 암에서 세포독성을 나타낸다고 보고 되어 왔으나 구강암에 대한 연구는 전혀 없다. 이에 본 연구에서는 구강암세포에서 오메가-3 지방산 중 DHA의 세포독성 기전을 규명하여 다음과 같은 결과를 얻었다. DHA는 구강암 세포주 SCC-4 및 SCC-9의 증식을 농도 의존적으로 억제하였으며, FACS 분석, TUNEL assay 및 PARP cleavage 등에 의해 자가사멸을 유도함이 확인 되었다. 또한 DHA는 LC-3II 단백증가, GFP-LC-3 dot 형성 및 autophagic flux assay 등에 의해 자가포식도 유도됨이 규명되었다. SCC-9 세포에서 AMPK의 인산화는 DHA 에 의해 증가 하였으나, p-$AKT^{Thr308}$, p-$AKT^{Ser473}$ 및 mTOR단백양은 감소하였다. 이상의 결과로 DHA는 구강암세포에서 AMPK 활성증가 및 AKT 억제에 통한 mTOR 신호경로 차단에 따른 자가사멸 및 자가포식에 의해 세포독성을 나타낼 수 있음을 시사하며, 따라서 DHA는 구강암의 예방 및 치료에 유용하게 사용될 수 있으리라 생각된다.

Keywords

References

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