Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy.
OBJECTIVE
Recently, the anti-apoptotic Mcl-1 protein has been reported as a resistance factor in various types of cancer. Here we investigated the presence of Mcl-1 protein in hepatocellular carcinoma (HCC) tissues and its potential role as a molecular drug target for HCC therapy.


METHODS
HCC specimens of 149 patients were examined by immunohistochemistry for Mcl-1 expression. Antisense oligonucleotides (ASO) targeting Mcl-1 were evaluated as monotherapy and in combination with cisplatin in the HCC cell lines HepG2 and Snu398. Protein regulation, cell viability, and apoptosis were assessed by western blotting, cell counting, and FACS analysis.


RESULTS
Mcl-1 protein is overexpressed in 51% of all cases irrespective of underlying disease. Targeting Mcl-1 by ASO specifically downregulated Mcl-1 protein expression and led to significant dose and time dependent single agent activity in HCC cells characterized by increased apoptosis and decreased cell viability. No significant target regulation or cell death was observed for control oligonucleotide treatment. Upon combination with cisplatin, Mcl-1 ASO revealed a significant chemosensitizing effect.


CONCLUSIONS
Mcl-1 is overexpressed in half of HCC-tissues. ASO targeting Mcl-1 revealed a prominent single agent and chemosensitizing activity against HCC in vitro. Targeting Mcl-1 might qualify as a promising novel approach in HCC therapy.
Sieghart
Wolfgang
W
Section of Experimental Oncology/Molecular Pharmacology, Department of Clinical Pharmacology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Losert
Doris
D
Strommer
Sabine
S
Cejka
Daniel
D
Schmid
Katharina
K
Rasoul-Rockenschaub
Susanne
S
Bodingbauer
Martin
M
Crevenna
Richard
R
Monia
Brett P
BP
Peck-Radosavljevic
Markus
M
Wacheck
Volker
V
D017209:Apoptosis; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002452:Cell Count; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm