Abstract
Sangivamycin has shown a potent antiproliferative activity against a variety of human cancers. However, little is known about the mechanism of action underlying its antitumor activity. Here we demonstrate that sangivamycin has differential antitumor effects in drug-sensitive MCF7/wild type (WT) cells, causing growth arrest, and in multidrug-resistant MCF7/adriamycin-resistant (ADR) human breast carcinoma cells, causing massive apoptotic cell death. Comparisons between the effects of sangivamycin on these two cell lines allowed us to identify the mechanism underlying the apoptotic antitumor effect. Fluorescence-activated cell sorter analysis indicated that sangivamycin induced cell cycle arrest in the G(2)/M phase in MCF7/ADR cells. A marked induction of c-Jun expression as well as phosphorylation of c-Jun and JNK was observed after sangivamycin treatment of MCF7/ADR cells but not MCF7/WT cells. Sangivamycin also induced cleavage of lamin A and poly(ADP-ribose) polymerase (PARP) in MCF7/ADR cells, probably via activation of caspase-6, -7, and -9. Pretreatment with a caspase-9-specific inhibitor or pan-caspase inhibitor abolished sangivamycin-induced cleavage of lamin A and PARP but not sangivamycin induction of c-Jun expression and phosphorylation. Pretreatment of MCF7/ADR cells with SP600125, a specific inhibitor of JNK, or with rottlerin, a specific inhibitor of protein kinase Cdelta (PKCdelta), significantly reduced the sangivamycin-induced apoptosis and almost completely abolished sangivamycin-induced phosphorylation of c-Jun and cleavage of lamin A and PARP. Transfection of MCF7/ADR cells with PKCdelta small interfering RNAs or PKCdelta antibody or rottlerin pretreatment significantly suppressed the phosphorylation of JNK. Taken together, our data suggest that sangivamycin induces mitochondria-mediated apoptotic cell death of MCF7/ADR cells via activation of JNK in a protein kinase Cdelta-dependent manner.
Highlights
MAY 18, 2007 VOLUME 282 NUMBER 20 nucleoside analog antibiotic originally isolated from Streptomyces rimosus, was found to have antiviral activity (1–2)
Cell Growth—To identify biological activities of sangivamycin relevant to its antitumor activity toward human breast carcinoma cells, we first compared the chemosensitivity of drug-sensitive human breast carcinoma MCF7/wild type (WT) cells and multisangivamycin by examining the cell growth rate and morphological changes
At 3 h post-transfection, cell culture medium was cells were treated with 0.1 M or higher concentrations of sansupplemented with a final concentration of 0.3 M sangiva- givamycin for 72 h, the number of viable cells was reduced to mycin or vehicle without removing the medium containing levels below that measured before the sangivamycin treatment, anti-PKC␦ and Chariot, and cells were continuously incu- implying a cytocidal effect toward MCF7/ADR cells
Summary
MAY 18, 2007 VOLUME 282 NUMBER 20 nucleoside analog antibiotic originally isolated from Streptomyces rimosus, was found to have antiviral activity (1–2). Pretreatment of MCF7/ADR cells with 20 M rottlerin, a specific inhibitor of PKC␦, for 1 h significantly reduced the induction of c-Jun expression and phosphorylation and suppressed the caspase-9 activation, cleavage of lamin A and PARP by sangivamycin (Fig. 5C).
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