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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
Manumycin induces apoptosis in human hepatocellular carcinoma HepG2 cells
Jun-Min Zhou1, Xiao-Feng Zhu, Qi-Chao Pan
1Cancer Institute, Cancer Center, Sun Yat-sen University, 651 DongFeng Road East, Guangzhou 510060, China.
Abstract:
Farnesyltransferase inhibitors (FTIs) were developed to prevent Ras processing and thus to be effective agents for the treatment of cancers harbouring mutated ras. In the present study, HepG2 cells underwent internucleosomal DNA fragmentation after treatment with farnesyltransferase inhibitor manumycin (20 microM) for 12 h. Flow cytometric analysis showed that HepG2 cells were accumulated in the G2/M phase of the cell cycle and the number of apoptotic sub-G1 fraction of cells was increased after treatment with manumycin in a time-dependent manner. During the induction of apoptosis, expression of p53 and p21WAF1 was upregulated, phosphorylation of IkappaB-alpha was blocked, caspase substrates poly(ADP-ribose) polymerase (PARP) and lamin B were cleaved, and Bcl-2 and Bax protein expression remained unchanged. These results indicated that manumycin induced apoptosis in HepG2 cells. The induction of apoptosis by manumycin involved the upregulation of p53 and p21WAF1, the activation of caspases, and the inhibition of nuclear factor-kappaB (NF-kappaB) pathway. However, Bcl-2 and Bax are not associated with manumycin-mediated apoptosis.
Insights
Farnesyltransferase inhibitor manumycin induces cancer cell death by triggering apoptosis. This process involves p53 and p21WAF1 upregulation, caspase activation, and NF-kappaB pathway inhibition in HepG2 cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Farnesyltransferase inhibitors (FTIs) target Ras processing for cancer treatment.
- Mutated ras genes are common in various cancers, necessitating effective therapeutic agents.
Purpose of the Study:
- To investigate the effects of farnesyltransferase inhibitor manumycin on HepG2 cells.
- To elucidate the molecular mechanisms underlying manumycin-induced apoptosis.
Main Methods:
- HepG2 cells were treated with manumycin (20 microM).
- Internucleosomal DNA fragmentation was assessed.
- Flow cytometry analyzed cell cycle distribution and apoptosis.
- Protein expression (p53, p21WAF1, IkappaB-alpha, PARP, lamin B, Bcl-2, Bax) and phosphorylation were evaluated.
Main Results:
- Manumycin induced internucleosomal DNA fragmentation and G2/M phase arrest in HepG2 cells.
- Apoptosis was evidenced by increased sub-G1 fraction, PARP, and lamin B cleavage.
- p53 and p21WAF1 expression increased, while IkappaB-alpha phosphorylation was blocked.
- Bcl-2 and Bax protein levels remained unchanged, indicating they are not involved.
Conclusions:
- Manumycin effectively induces apoptosis in HepG2 cells.
- The apoptotic pathway involves p53 and p21WAF1 upregulation and caspase activation.
- Inhibition of the nuclear factor-kappaB (NF-kappaB) pathway contributes to manumycin-mediated apoptosis.
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