Involvement of Sox-4 in the cytochrome c-dependent AIF-independent apoptotic pathway in HeLa cells induced by Delta12-prostaglandin J2.
Delta(12)-Prostaglandin (PG) J(2) is known to elicit an anti-neoplastic effects via apoptosis induction. Previous study showed Delta(12)-PGJ(2)-induced apoptosis utilized caspase cascade through cytochrome c-dependent pathways in HeLa cells. In this study, the cellular mechanism of Delta(12)-PGJ(2)- induced apoptosis in HeLa cells, specifically, the role of two mitochondrial factors; bcl-2 and apoptosis-inducing factor (AIF) was investigated. Bcl-2 attenuated Delta(12)-PGJ(2)-induced caspase activation, loss of mitochondrial transmembrane potential (Deltapsi(m)), nuclear fragmentation, DNA laddering, and growth curve inhibition for approximately 24 h, but not for longer time. AIF was not released from mitochondria, even if the Deltapsi(m) was dissipated. One of the earliest events observed in Delta(12)-PGJ(2)-induced apoptotic events was dissipation of Deltapsi(m), the process known to be inhibited by bcl-2. Pre-treatment of z-VAD- fmk, the pan-caspase inhibitor, resulted in the attenuation of ym depolarization in Delta(12)-PGJ(2)-induced apoptosis. Up-regulation of Sox-4 protein by Delta(12)-PGJ(2) was observed in HeLa and bcl-2 overexpressing HeLa B4 cell lines. Bcl-2 overexpression did not attenuate the expression of Sox-4 and its expression coincided with other apoptotic events. These results suggest that Delta(12)-PGJ(2) induced Sox-4 expression may activate another upstream caspases excluding the caspase 9-caspase 3 cascade of mitochondrial pathway. These and previous findings together suggest that Delta(12)-PGJ(2)-induced apoptosis in HeLa cells is caspase-dependent, AIF-independent events which may be affected by Sox-4 protein expression up-regulated by Delta(12)-PGJ(2).
Kim
Boe-Eun
BE
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Lee
Jeong-Hwa
JH
Kim
Ho-Shik
HS
Kwon
Oh-Joo
OJ
Jeong
Seong-Whan
SW
Kim
In-Kyung
IK
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000502:physiology; D045304:Cytochromes c / Q000502:physiology; D005260:Female; D005420:Flavoproteins / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D015230:Prostaglandin D2 / Q000494:pharmacology*; D021381:Protein Transport / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D055751:SOXC Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation
C494829:AIFM1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D006609:High Mobility Group Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D015534:Trans-Activators; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C499810:delta(12)-prostaglandin J(2); D045304:Cytochromes c; D020169:Caspases; D015230:Prostaglandin D2