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Research Article Free access | 10.1172/JCI119078

Selective induction of apoptosis in Hep 3B cells by topoisomerase I inhibitors: evidence for a protease-dependent pathway that does not activate cysteine protease P32.

P N Adjei, S H Kaufmann, W Y Leung, F Mao, and G J Gores

Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Find articles by Adjei, P. in: JCI | PubMed | Google Scholar

Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

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Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

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Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Find articles by Mao, F. in: JCI | PubMed | Google Scholar

Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Find articles by Gores, G. in: JCI | PubMed | Google Scholar

Published December 1, 1996 - More info

Published in Volume 98, Issue 11 on December 1, 1996
J Clin Invest. 1996;98(11):2588–2596. https://doi.org/10.1172/JCI119078.
© 1996 The American Society for Clinical Investigation
Published December 1, 1996 - Version history
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Abstract

Progress in the treatment of hepatocellular carcinoma (HCC), a common tumor worldwide, has been disappointing. Inhibitors of topoisomerases are being widely studied as potential inducers of tumor cell apoptosis. Our aims were to determine whether topoisomerase-directed drugs would induce apoptosis in a human HCC cell line (Hep 3B) and, if so, to investigate the mechanism. The topoisomerase I poison camptothecin (CPT) induced apoptosis of Hep 3B cells in a time- and concentration-dependent manner. In contrast, the topoisomerase II poison etoposide failed to induce apoptosis despite the apparent stabilization of topoisomerase II-DNA complexes. Unexpectedly, CPT-induced apoptosis in this cell type occurred without any detectable cleavage of poly(ADP-ribose) polymerase or lamin B, polypeptides that are commonly cleaved in other cell types undergoing apoptosis. Likewise, Hep 3B cell apoptosis occurred without a detectable increase in interleukin-1beta-converting enzyme (ICE)-like or cysteine protease P32 (CPP32)-like protease activity. In contrast, trypsin-like protease activity (cleavage of Boc-Val-Leu-Lys-chloromethylaminocoumarin in situ) increased threefold in cells treated with CPT but not etoposide. Tosyl-lysyl chloromethyl ketone inhibited the trypsin-like protease activity and diminished CPT-induced apoptosis. These data demonstrate that (a) apoptosis is induced in Hep 3B cells after stabilization of topoisomerase I-DNA complexes but not after stabilization of topoisomerase II-DNA complexes as measured by alkaline filter elution; (b) Hep 3B cell apoptosis occurs without activation of ICE-like and CPP32-like protease activity; and (c) a trypsin-like protease activity appears to contribute to apoptosis in this cell type.

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