Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 33, Issue 9, Pages 1620-1626Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.33.1620
Keywords
3 alpha,23-isopropylidenedioxyolean-12-en-27-oic acid; apoptosis; HeLa cell; endoplasmic reticulum stress; mitochondrial dysfunction; caspase
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Funding
- Ministry of Education, Science and Technology [2009-0088135]
- National Research Foundation of Korea [2009-0088135] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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In the present study, we investigated the effect of 3 alpha,23-isopropylidenedioxyolean-12-en-27-oic acid (IPA), an active compound isolated from Aceriphyllunt rossii, on the apoptotic activity and the molecular mechanism of the action in human cervical cancer HeLa cells. Treatment with IPA significantly increased externalization of phosphatidylserine residues and apoptotic DNA fragmentation as shown by Annexin V staining and 4',6-diamidino-2-phenylindole-dihydrochloride (DAPI) staining, respectively. In addition, IPA induced the activations of caspase-8, -9, -3, and cleavage of poly(ADP ribose) polymerase (PARP-1) in HeLa cells. Pretreatment with a specific caspase-8, -9, or -3 inhibitor neutralized the pro-apoptotic activity of IPA in HeLa cells. Furthermore, IPA was found to induce the loss of mitochondrial membrane potential, the release of cytochrome c to the cytosol, and the increased ratio of mitochondrial Bax/Bc1-2. Moreover, we demonstrated that IPA triggered endoplasmic reticulum (ER) stress, as shown by changes in cytosol-calcium level, activation of mu-calpain and caspase-12, and up-regulation of glucose-regulated protein 78 (GRP78) and growth arrest DNA damage-inducible gene 153 (GADD153). IPA-induced apoptosis was substantially reduced in the presence of an intracellular calcium chelator BAPTA/AM. Taken together, these results suggest that both mitochondrial dysfunction and ER stress contribute to IPA-induced apoptosis of human cervical cancer HeLa cells.
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