Induction of apoptosis by the proteasome inhibitor MG132 in human HCC cells: Possible correlation with specific caspase-dependent cleavage of β-catenin and inhibition of β-catenin-mediated transactivation

Natale D'Alessandro, Giuseppe Montalto, Manuela Labbozzetta, Monica Notarbartolo Di Villarosa, Lydia Giannitrapani, Paola Poma, Massimo La Rosa, Monica Notarbartolo, Marzia La Rosa, Natale D'Alessandro, Giuseppe Montalto, Paola Poma, Manuela Labbozzetta, Melchiorre Cervello, Lydia Giannitrapani

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Abstract

Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.
Lingua originaleEnglish
pagine (da-a)741-748
Numero di pagine8
RivistaInternational Journal of Molecular Medicine
Volume13
Stato di pubblicazionePublished - 2004

All Science Journal Classification (ASJC) codes

  • Genetics

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title = "Induction of apoptosis by the proteasome inhibitor MG132 in human HCC cells: Possible correlation with specific caspase-dependent cleavage of β-catenin and inhibition of β-catenin-mediated transactivation",
abstract = "Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.",
author = "Natale D'Alessandro and Giuseppe Montalto and Manuela Labbozzetta and {Notarbartolo Di Villarosa}, Monica and Lydia Giannitrapani and Paola Poma and {La Rosa}, Massimo and Monica Notarbartolo and {La Rosa}, Marzia and Natale D'Alessandro and Giuseppe Montalto and Paola Poma and Manuela Labbozzetta and Melchiorre Cervello and Lydia Giannitrapani",
year = "2004",
language = "English",
volume = "13",
pages = "741--748",
journal = "International Journal of Molecular Medicine",
issn = "1107-3756",
publisher = "Spandidos Publications",

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TY - JOUR

T1 - Induction of apoptosis by the proteasome inhibitor MG132 in human HCC cells: Possible correlation with specific caspase-dependent cleavage of β-catenin and inhibition of β-catenin-mediated transactivation

AU - D'Alessandro, Natale

AU - Montalto, Giuseppe

AU - Labbozzetta, Manuela

AU - Notarbartolo Di Villarosa, Monica

AU - Giannitrapani, Lydia

AU - Poma, Paola

AU - La Rosa, Massimo

AU - Notarbartolo, Monica

AU - La Rosa, Marzia

AU - D'Alessandro, Natale

AU - Montalto, Giuseppe

AU - Poma, Paola

AU - Labbozzetta, Manuela

AU - Cervello, Melchiorre

AU - Giannitrapani, Lydia

PY - 2004

Y1 - 2004

N2 - Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.

AB - Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.

UR - http://hdl.handle.net/10447/30219

M3 - Article

VL - 13

SP - 741

EP - 748

JO - International Journal of Molecular Medicine

JF - International Journal of Molecular Medicine

SN - 1107-3756

ER -