Signaling events in apoptotic photokilling of 5-aminolevulinic acid-treated tumor cells: Inhibitory effects of nitric oxide

Reshma Bhowmick, Albert W. Girotti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Antitumor photodynamic therapy (PDT) employs a photosensitizing agent, molecular oxygen, and visible light to produce reactive oxygen species that can destroy tumor and tumor vasculature cells. NO produced by these cells could be procarcinogenic by inhibiting apoptosis and promoting angiogenesis and tumor growth. We recently showed that NO from a chemical donor or activated macrophages makes COH-BR1 breast tumor cells more resistant to photokilling sensitized by 5-aminolevulinic acid (ALA)-generated protoporphyrin IX (PpIX). Signaling events associated with this hyperresistance have now been examined. ALA-treated COH-BR1 cells containing mitochondria-localized PpIX died mainly by apoptosis after being irradiated. Underlying redox signaling associated with MAP kinase (ERK1/2, p38, JUN) phosphorylation-activation, and heme oxygenase-1 (HO-1) upregulation was studied using immunoprecipitation and Western blot methodology. ALA/light treatment resulted in activation of proapoptotic JNK and p38α, and deactivation of prosurvival p38β and ERK1/2. Involvement of both JNK and p38 in apoptosis was established by using a specific inhibitor for each. Spermine NONOate-derived NO, introduced immediately before irradiation, provided substantial protection against apoptosis. This was accompanied by greater HO-1 induction and a strong inhibition of each MAP kinase effect seen in the absence of NO. Downstream of JNK and p38α activation, a marked upregulation/activation of proapoptotic Bax and Bid was observed along with down-regulation of antiapoptotic Bcl-xL, each response being reversed by NO. These findings provide new insights into signaling activity associated with the intrinsic apoptotic pathway in ALA-PDT and how this activity can be modulated by NO.

Original languageEnglish (US)
Pages (from-to)731-740
Number of pages10
JournalFree Radical Biology and Medicine
Volume47
Issue number6
DOIs
StatePublished - Sep 15 2009

Keywords

  • 5-Aminolevulinic acid
  • Apoptosis
  • Mitogen-activated protein kinase (MAPK)
  • Nitric oxide
  • Photodynamic therapy
  • Redox signaling
  • Tumor cells

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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