論文

査読有り
2005年9月

Activation of protein kinase G up-regulates expression of 15-lipoxygenase-1 in human colon cancer cells

CANCER RESEARCH
  • A Deguchi
  • ,
  • SW Xing
  • ,
  • Shureiqi, I
  • ,
  • PY Yang
  • ,
  • RA Newman
  • ,
  • SM Lippman
  • ,
  • SJ Feinmark
  • ,
  • B Oehlen
  • ,
  • IB Weinstein

65
18
開始ページ
8442
終了ページ
8447
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/0008-5472.CAN-05-1109
出版者・発行元
AMER ASSOC CANCER RESEARCH

Recent studies indicate that the induction of apoptosis in human colon cancer cells by certain nonsteroidal antiinflammatory drugs involves increased expression of 15-LOX-1 and synthesis of its major product 13-S-hydroxyoctadecadienoic acid (13-S-HODE). Evidence was obtained that this occurs via a cyclooxygenase-2 (COX-2)-independent mechanism, but the actual mechanism of induction of 15-LOX-1 by these compounds is not known. There is extensive evidence that treatment of SW480 human colon cancer cells with sulindac sulfone (Exisulind, Aptosyn) or the related derivative OSI-461, both of which inhibit cyclic GMP (cGMP)-phosphodiesterases but lack COX-2 inhibitory activity, causes an increase in intracellular levels of cGMP, thus activating protein kinase G (PKG), which then activates pathways that lead to apoptosis. Therefore, in the present study, we examined the effects of various agents that cause increased cellular levels of cGMP on the expression of 15-LOX-1 in SW480 human colon cancer cells. Treatment of the cells with Exisulind, sulindac sulfide, OSI-461, the guanylyl cyclase activator YC-1, or the cefl-permeable cGMP compound 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) caused an increase in cellular levels of 15-LOX-1. Exisulind, OSI-461, and 8-pCPT-cGMP also increased mRNA levels of 15-LOX-1, suggesting that the effects were at the level of transcription. The cGMP-phosphodiesterase inhibitors and YC-1 increased the production of 13-S-HODE, which is the linoleic acid metabolite of 15-LOX-1. Treatment of SW480 cells with the PKG inhibitor Rp-8-pCPT-cGM[P blocked Exisulind-induced 15-LOX-1 expression. Furthermore, derivatives of SW480 cells that were engineered to stably overexpress wildtype PKG 1 displayed increased cellular levels of 15-LOX-1 when compared with vector control cells. Taken together, these results provide evidence that the cGMP/PKG pathway can play an important role in the induction of 15-LOX-1 expression by nonsteroidal antiinfiammatory drugs and related agents.

Web of Science ® 被引用回数 : 33

リンク情報
DOI
https://doi.org/10.1158/0008-5472.CAN-05-1109
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/16166323
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000231848800048&DestApp=WOS_CPL

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