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Involvement of caspase-9 in autophagy-mediated cell survival pathway.

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered for use in the prevention and treatment of cancer malignancy. FR122047 (FR) is known to have an anti-inflammatory effect, but the anticancer activity of the chemical has not yet been identified. In the present study, we could find that treatment of breast cancer MCF-7 cells with FR led to apoptosis accompanying with apparent activation of caspases. Treatment of caspase-specific inhibitors revealed that FR-induced apoptosis was caspase-8-dependent and inhibition of caspase-9 activity resulted in unexpected, marked enhancement of cell death. Knockdown of caspase-9 expression by specific siRNA caused increased susceptibility to FR-induced cell death, consistent with the results obtained with treatment of caspase-9 inhibitor. Inhibition of caspase-9 blocked the autophagic process by modulating lysosomal pH and acid-dependent cathepsin activities and augmented cell death due to blockage of cytoprotective autophagy. MCF-7 cells treated with sulforaphane, an autophagy-inducing drug, also showed marked accumulation of LC3-II, and co-treatment with caspase-9 inhibitor brought about increased susceptibility to sulforaphane-induced cell death. Different from the cases with FR or sulforaphane, etoposide- or doxorubicin-induced cell death was suppressed with co-treatment of caspase-9 inhibitor, and the drugs failed to induce significant autophagy in MCF-7 cells. Taken together, our data originally suggest that inhibition of caspase-9 may block the autophagic flux and enhance cell death due to blockage of cytoprotective autophagy.
AuthorsHyo-Soon Jeong, Hye Yeon Choi, Eung-Ryoung Lee, Jung-Hyun Kim, Kilsoo Jeon, Hyun-Joo Lee, Ssang-Goo Cho
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1813 Issue 1 Pg. 80-90 (Jan 2011) ISSN: 0006-3002 [Print] Netherlands
PMID20888374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier B.V. All rights reserved.
Chemical References
  • Antibiotics, Antineoplastic
  • Anticarcinogenic Agents
  • Antineoplastic Agents, Phytogenic
  • Caspase Inhibitors
  • Isothiocyanates
  • RNA, Messenger
  • RNA, Small Interfering
  • Thiocyanates
  • sulforafan
  • Etoposide
  • Doxorubicin
  • Caspase 9
Topics
  • Antibiotics, Antineoplastic (pharmacology)
  • Anticarcinogenic Agents (pharmacology)
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Apoptosis (drug effects)
  • Autophagy
  • Blotting, Western
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Caspase 9 (genetics, metabolism)
  • Caspase Inhibitors
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Cytoplasm (metabolism)
  • Doxorubicin (pharmacology)
  • Enzyme Activation (drug effects)
  • Etoposide (pharmacology)
  • Female
  • Flow Cytometry
  • Humans
  • Isothiocyanates
  • Mitochondria (metabolism)
  • RNA, Messenger (genetics)
  • RNA, Small Interfering (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Thiocyanates (pharmacology)
  • Tumor Cells, Cultured

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