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

  • Authors:
    • Melchiorre Cervello
    • Lydia Giannitrapani
    • Marzia La Rosa
    • Monica Notarbartolo
    • Manuela Labbozzetta
    • Paola Poma
    • Giuseppe Montalto
    • Natale D'Alessandro
  • View Affiliations

  • Published online on: May 1, 2004     https://doi.org/10.3892/ijmm.13.5.741
  • Pages: 741-748
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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. β-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 β-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G2/M phases of the cell cycle, as well as with fragmentation of β-catenin (but not of α- or γ-catenin) in all the cell lines. The cleavage of β-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented β-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/β-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.

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May 2004
Volume 13 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Cervello M, Giannitrapani L, La Rosa M, Notarbartolo M, Labbozzetta M, Poma P, Montalto G and D'Alessandro N: 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. Int J Mol Med 13: 741-748, 2004
APA
Cervello, M., Giannitrapani, L., La Rosa, M., Notarbartolo, M., Labbozzetta, M., Poma, P. ... D'Alessandro, N. (2004). 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. International Journal of Molecular Medicine, 13, 741-748. https://doi.org/10.3892/ijmm.13.5.741
MLA
Cervello, M., Giannitrapani, L., La Rosa, M., Notarbartolo, M., Labbozzetta, M., Poma, P., Montalto, G., D'Alessandro, N."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". International Journal of Molecular Medicine 13.5 (2004): 741-748.
Chicago
Cervello, M., Giannitrapani, L., La Rosa, M., Notarbartolo, M., Labbozzetta, M., Poma, P., Montalto, G., D'Alessandro, N."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". International Journal of Molecular Medicine 13, no. 5 (2004): 741-748. https://doi.org/10.3892/ijmm.13.5.741