title: Effect of alteration of caveolin-1 expression on doxorubicin-induced apoptosis in H9c2 cardiac cells.
abstract: Doxorubicin is an anthracycline antibiotic widely used in cancer treatment. Although its antitumor efficacy appears to be dose dependent, its clinical use is greatly restricted by the development of cardiotoxicity associated with apoptosis. Although caveolin-1, the major structural protein in caveolae, can positively or negatively regulate apoptosis depending on the stimulus or cell types, the contribution of caveolin-1 to doxorubicin-induced apoptosis remains unknown. This study was performed to identify the regulatory role of caveolin-1 on doxorubicin-induced apoptosis in H9c2 cardiac cells using a genetic approach. Caveolin-1 knockdown with a short hairpin (sh) RNA adenovirus, but not overexpression of wild-type caveolin-1, resulted in a marked inhibition of doxorubicin-induced caspase-3 cleavage. However, caveolin-1 knockdown tended to protect against doxorubicin-induced decrease in cell viability, but it did not significantly reverse cell death induced by doxorubicin. Doxorubicin stimulated the phosphorylation of p38 and extracellular signal regulated kinase (ERK). Doxorubicin-induced caspase-3 cleavage was inhibited by U0126, a MEK inhibitor or SB203580, a p38 inhibitor. Caveolin-1 knockdown markedly inhibited doxorubicin-induced p-38 phosphorylation but not ERK-mediated p-53 phosphorylation in H9c2 cardiac cells. Our results suggest that reduced caveolin-1 expression plays an anti-apoptotic role in doxorubicin-induced apoptosis but that it is insufficient to prevent such an apoptosis in H9c2 cardiac cells.
authors: Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru, 047-0264, Japan.
authors: Akira
authors: A
authors: Takaguri
authors: Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru, 047-0264, Japan.
authors: Maiko
authors: M
authors: Kamato
authors: Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru, 047-0264, Japan.
authors: Yoshiaki
authors: Y
authors: Satoh
authors: Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru, 047-0264, Japan.
authors: Kazuaki
authors: K
authors: Ohtsuki
authors: Division of Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy, 7-1 Katsuraoka, Otaru, 047-0264, Japan.
authors: Kumi
authors: K
authors: Satoh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D051242:Caveolin 1; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3
keywords: MAP kinase family members; apoptosis; caspase-3; caveolin-1; doxorubicin