Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Reactive Oxygen Species Mediates Lysophosphatidic Acid-induced Migration of SKOV-3 Ovarian Cancer Cells

SKOV-3 난소암 세포주에서 lysophosphatidic acid 유도 세포의 이동에 있어 활성산소의 역할

  • Kim, Eun Kyoung (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Lee, Hye Sun (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Ha, Hong Koo (Department of Urology, Pusan National University Hospital) ;
  • Yun, Sung Ji (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Ha, Jung Min (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Kim, Young Whan (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Jin, In Hye (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine) ;
  • Shin, Hwa Kyoung (Department of Anatomy, Pusan National University School of Korean Medicine) ;
  • Bae, Sun Sik (MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University School of Medicine)
  • 김은경 (부산대학교 의학전문대학원 약리학교실) ;
  • 이혜선 (부산대학교 의학전문대학원 약리학교실) ;
  • 하홍구 (부산대학교병원 비뇨기과학교실) ;
  • 윤성지 (부산대학교 의학전문대학원 약리학교실) ;
  • 하정민 (부산대학교 의학전문대학원 약리학교실) ;
  • 김영환 (부산대학교 의학전문대학원 약리학교실) ;
  • 진인혜 (부산대학교 의학전문대학원 약리학교실) ;
  • 신화경 (부산대학교 한의학전문대학원 해부학교실) ;
  • 배순식 (부산대학교 의학전문대학원 약리학교실)
  • Received : 2012.11.13
  • Accepted : 2012.12.04
  • Published : 2012.12.30
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Abstract

Cell motility plays an essential role in many physiological responses, such as development, immune reaction, and angiogenesis. In the present study, we showed that lysophosphatidic acid (LPA) modulates cancer cell migration by regulation of generation of reactive oxygen species (ROS). Stimulation of SKOV-3 ovarian cancer cells with LPA strongly promoted migration. but this migration was completely blocked by pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Inhibition of the ERK pathway had no effect on migration. Stimulation of SKOV-3 ovarian cancer cells with LPA significantly induced the generation of ROS in a time-dependent manner. LPA-induced generation of ROS was significantly blocked by pharmacological inhibition of PI3K or Akt, but inhibition of the ERK signaling pathway had little effect. LPA-induced generation of ROS was blocked by pretreatment of SKOV-3 ovarian cancer cells with an NADPH oxidase inhibitor, whereas inhibition of xanthine oxidase, cyclooxygenase, or mitochondrial respiratory chain complex I had no effect. Scavenging of ROS by N-acetylcysteine completely blocked LPA-induced migration of SKOV-3 ovarian cancer cells. Inhibition of NADPH oxidase blocked LPA-induced migration whereas inhibition of xanthine oxidase, cyclooxygenase, or mitochondrial respiratory chain complex I did not affect LPA-induced migration of SKOV-3 ovarian cancer cells. Given these results, we suggest that LPA induces ROS generation through the PI3K/Akt/NADPH oxidase signaling axis, thereby regulating cancer cell migration.

세포의 이동은 성장, 면역 작용, 그리고 혈관 신생 등 많은 생리현상에 중요한 역할을 한다. 또한 염증 및 종양 세포 침윤 등의 다양한 병리적 현상과도 밀접한 연관이 있다. 본 연구에서는 lysophosphatidic acid (LPA)는 활성산소의 생성을 통해 SKOV-3 난소암세포의 이동을 조절한다는 것을 관찰하였다. 먼저, 난소 암세포인 SKOV-3에서 LPA에 의한 세포의 이동이 강하게 일어남을 확인하였다. LPA에 의한 SKOV-3 세포의 이동은 phosphatidylinositol 3-kinase (PI3K)/Akt 신호전달체계를 저해시키는 약물에 의해서 완벽히 억제됨을 확인하였으나 ERK 신호전달체계를 저해시키는 약물에 의해서는 전혀 영향을 받지 않았다. 그리고 SKOV-3 세포에서 LPA에 의한 활성산소 형성이 시간에 따라 강하게 일어남을 확인하였다. 더욱이 LPA에 의한 활성산소 형성도 PI3K 또는 Akt의 저해제에 의해서 완벽히 억제됨을 확인하였으나 ERK 신호전달을 억제하였을 때는 거의 영향을 받지 않았다. SKOV-3 세포에서 LPA에 의해 생성된 활성산소는 diphenylene idonium (DPI, $10{\mu}M$), apocyanin (Apo, $10{\mu}M$)과 같은 NADPH oxidase 억제제를 전 처리하였을 때 활성산소가 형성되지 못함을 관찰하였다. 그러나 xanthine oxidase (allopurinol, Allo, $10{\mu}M$), cyclooxygenase (indomethacin, Indo, $10{\mu}M$), 또는 mitochondrial respiratory chain complex I (rotenone, Rot, $10{\mu}M$)를 억제하였을 때는 LPA에 의한 활성산소 형성에 영향을 주지 못함을 확인하였다. 마지막으로 활성산소 억제제인 N-acetylcysteine (NAC, $10{\mu}M$)에 의해서 LPA에 의한 암세포의 이동이 억제됨을 관찰하였다. 이와 더불어 LPA에 의한 SKOV-3 세포의 이동도 NADPH oxidase 억제에 의해 저해가 됨을 확인하였다. 이러한 연구결과로 보아 LPA에 의한 활성산소의 형성에는 PI3K/Akt/NADPH oxidase 신호전달체계가 중추적인 역할을 하며 이를 통해 암세포의 이동을 조절한다는 것을 알 수 있었다.

Keywords

References

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