Prostaglandin A₂-induced Apoptosis is Not Inhibited by Heme Oygenase-1 in U2OS Cells

국문 초록 (Abstract)

Prostaglandin A₂ (PGA₂)는 사람 골육종 세포인 U2OS 세포주에서 apoptosis와 heme oxygenase (HO)-1의 발현을 함께 유도하였다. PGA₂에 의한 apoptosis는 HO-1의 과도한 발현이나 HO-1에 대한 small interfering RNA에 의한 발현저하에 의하여 변동되지 않았으나 H₂O₂에 의한 세포사망은 HO-1의 발현 수준에 반비례하여 변동되었다. 또한 thiol antioxidant인 N-acetyl-L-cysteine (NAC)은 PGA₂에 의한 세포사망과 HO-1의 발현 증가를 모두 차단하였지만, non-thiol antioxidant인 butylated hydroxyanisole (BHA)과 ascorbic acid는 세포사망과 HO-1의 발현 유도를 차단하지 않았다. 이와 같은 결과들은 PGA₂는 산화성 손상에 의해서가 아니라 PGA₂의 thiol-reactivity에 의하여 apoptosis와 HO-1의 발현을 유도하며, HO-1의 발현은 PGA₂에 의한 apoptosis와는 독립적인 현상이거나 기능적으로 apoptosis 유도의 하부에 위치하고 apoptosis의 진행에는 기여하지 않을 것이라는 것을 시사해 준다.

다국어 초록 (Multilingual Abstract)

Prostaglandin A₂ (PGA₂), one of cyclopentenone PGs, induced both apoptosis and heme oxygenase (HO)-1 expression in U2OS cells. PGA₂-induced apoptosis was not perturbed by either over-expression or knock-down of HO-1, whereas H₂O₂-induced cell death was inversely modulated by the expression level of HO-1. In addition, N-acetyl-L-cysteine (NAC), a thiol antioxidant, blocked both apoptosis and HO-1 expression induced by PGA₂. But, non-thiol antioxidants like butylated hydorxyanisole (BHA) and ascorbic acid did not block either apoptosis or HO-1-induction. Taken together, these results suggest that PGA₂ induces both apoptosis and HO-1 expression, which are critically related to the thiol-reactivity of PGA₂, but not oxidative stress, and HO-1 expression may be independent or functionally located downstream of apoptosis by PGA₂ without contribution to apoptosis progression.

목차 (Table of Contents)

• Introduction
• Materials and Methods
• Results
• Discussion
• Acknowledgement
• References
• 초록

참고문헌 (Reference)

1 Alam, J, "Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway" 9 : 2499-2511, 2003

2 Ahn, S. G., "The role of c-Myc and heat shock protein 70 in human hepatocarcinoma Hep3B cells during apoptosis induced by prostaglandin A2/Delta12-prostaglandin J2" 1448 : 115-125, 1998

3 Kim, H, "Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin" 60 : 47-56, 2008

4 Narumiya, S., "Site and mechanism of growth inhibition by prostaglandins. III. Distribution and binding of prostaglandin A2 and delta 12-prostaglandin J2 in nuclei" 242 : 306-311, 1987

5 Narumiya, S., "Site and mechanism of growth inhibition by prostaglandins. II. Temperature-dependent transfer of a cyclopentenone prostaglandin to nuclei" 239 : 506-511, 1986

6 Zhuang, H., "Regulation of heme oxygenase expression by cyclopentenone prostaglandins" 228 : 499-505, 2003

7 Poss, K D, "Reduced stress defense in heme oxygenase I-deficient cells" 94 : 10925-10930, 1997

8 Sanchez-Gomez, F. L, "Protein thiol modification by 15-deoxy-Delta12)4-prostaglandin J2 addition in mesangial cells: role in the inhibition of pro-inflammatory genes" 66 : 1349-1358, 2004

9 Chen, Y. c., "Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species" 1743 : 291-304, 2005

10 김호식, "Prostaglandin A2에 의한 간세포암종 세포의 Caspase-비의존적 Apoptosis 유도" 대한간학회 11 (11): 72-79, 2005

11 Kim, I. K, "Prostaglandin A2 and delta 12-prostaglandin J2 induce apoptosis in 11210 cells" 321 : 209-214, 1993

12 Li Volti, G, "Pharmacological induction of heme oxygenase-1 inhibits iNOS and oxidative stress in renal ischemia-reperfusion injury" 39 : 2986-2991, 2007

13 Lee, P. L, "Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia" 93 : 10393-10398, 1996

14 Lee, J. S, "Nrf2 as a novel molecular target for chemoprevention" 224 : 171-184, 2005

15 Kim, H S., "Intracellular glutathione level modulates the induction of apoptosis by delta 12-prostaglandin J2" 51 : 413-425, 1996

16 Gorospe, M., "Inhibition of G1 cyclin-dependent kinase activity during growth arrest of human breast carcinoma cells by prostaglandin A2" 16 : 762-770, 1996

17 Lee, J. H, "Induction of p53 and apoptosis by delta 12-PGJ2 in human hepatocarcinoma SK-HEP-1 cells" 368 : 348-352, 1995

18 Kim, H S., "Induction of apoptosis dependent on caspase activities and growth arrest in HL-60 cells by PGA2" 70 : 169-183, 2002

19 Holbrook N. L, "Induction of HSP70 gene expression by the antiproliferative prostaglandin PGA2: a growth-dependent response mediated by activation of heat shock transcription factor" 12 : 1528-1534, 1992

20 Radhakrishnan, N., "Hepatocyte growth factor modulates H202-induced mesangial cell apoptosis through induction of heme oxygenase-I" 101 : 92-98, 2005

21 Ryter, S. W., "Heme oxygenase/ carbon monoxide signaling pathways: regulation and functional significance" 234-235 : 249-263, 2002

22 Otterbein, L. E., "Heme oxygenase-I: unleashing the protective properties of heme" 24 : 449-455, 2003

23 Parker, J, "Formation of a prostaglandin A2-glutathione conjugate in 11210 mouse leukemia cells" 43 : 1053-1060, 1992

24 Ohno, K, "Effect of glutathione content on cellular uptake and growth inhibitory activity of prostaglandin A2 in L-1210 cells" 5 : 81-85, 1992

25 Straus, D. S, "Cyclopentenone prostaglandins: new insights on biological activities and cellular targets" 21 : 185-210, 2001

26 Nencioni, A, "Cyclopentenone prostaglandins induce lymphocyte apoptosis by activating the mitochondrial apoptosis pathway independent of external death receptor signaling" 171 : 5148-5156, 2003

27 Choi, AM, "Cell growth inhibition by prostaglandin A2 results in elevated expression of gadd153 mRNA" 199 : 85-89, 1992

28 Hubich, A I, "Biochemistry of prostaglandins A" 71 : 229-238, 2006

29 Rossi, A, "Anti-inflammatory cyclo pentenone prostaglandins are direct inhibitors of IkappaB kinase" 403 : 103-108, 2000

30 Livak K J, "Analysis of relative gene expression data using real-time quantitative PCR and the 2(-flflC(T)) method" 25 : 402-408, 2001

31 Kobayashi, M., "ATM activation by a sulfhydryl-reactive inflammatory cyclopentenone prostaglandin" 11 : 779-789, 2006

32 Alvarez-Maqueda, M., "15-deoxy-delta 12,14-prostaglandin J2 induces heme oxygenase-1 gene expression in a reactive oxygen species-dependent manner in human lymphocytes" 279 : 21929-21937, 2004