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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
Published on: June 29, 2011
RCC2 over-expression in tumor cells alters apoptosis and drug sensitivity by regulating Rac1 activation
1Department of Medical Genetics, Harbin Medical University, Harbin, China.
Background:
Small GTP binding protein Rac1 is a component of NADPH oxidases and is essential for superoxide-induced cell death. Rac1 is activated by guanine nucleotide exchange factors (GEFs), and this activation can be blocked by regulator of chromosome condensation 2 (RCC2), which binds the switch regions of Rac1 to prevent access from GEFs.
Methods:
Three cancer cell lines with up- or down-regulation of RCC2 were used to evaluate cell proliferation, apoptosis, Rac1 signaling and sensitivity to a group of nine chemotherapeutic drugs. RCC2 expression in lung cancer and ovarian cancer were studied using immunochemistry stain of tumor tissue arrays.
Results:
Forced RCC2 expression in tumor cells blocked spontaneous- or Staurosporine (STS)-induced apoptosis. In contrast, RCC2 knock down in these cells resulted in increased apoptosis to STS treatment. The protective activity of RCC2 on apoptosis was revoked by a constitutively activated Rac1, confirming a role of RCC2 in apoptosis by regulating Rac1. In an immunohistochemistry evaluation of tissue microarray, RCC2 was over-expressed in 88.3% of primary lung cancer and 65.2% of ovarian cancer as compared to non-neoplastic lung and ovarian tissues, respectively. Because chemotherapeutic drugs can kill tumor cells by activating Rac1/JNK pathway, we suspect that tumors with RCC2 overexpression would be more resistant to these drugs. Tumor cells with forced RCC2 expression indeed had significant difference in drug sensitivity compared to parental cells using a panel of common chemotherapeutic drugs.
Conclusions:
RCC2 regulates apoptosis by blocking Rac1 signaling. RCC2 expression in tumor can be a useful marker for predicting chemotherapeutic response.
Insights
Regulator of chromosome condensation 2 (RCC2) blocks Rac1 signaling, protecting cancer cells from apoptosis. Overexpression of RCC2 in lung and ovarian cancers suggests it may predict resistance to chemotherapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Small GTP binding protein Rac1 is crucial for NADPH oxidase function and superoxide-induced cell death.
- Regulator of chromosome condensation 2 (RCC2) inhibits Rac1 activation by binding its switch regions, preventing guanine nucleotide exchange factor (GEF) access.
Purpose of the Study:
- To investigate the role of RCC2 in cancer cell apoptosis and its relationship with Rac1 signaling.
- To evaluate RCC2 expression in lung and ovarian cancers.
- To determine if RCC2 expression influences sensitivity to chemotherapeutic drugs.
Main Methods:
- Utilized three cancer cell lines with altered RCC2 expression to assess proliferation, apoptosis, Rac1 signaling, and drug sensitivity.
- Employed immunohistochemistry on tumor tissue arrays to study RCC2 expression in lung and ovarian cancers.
Main Results:
- Forced RCC2 expression inhibited spontaneous and Staurosporine (STS)-induced apoptosis, while RCC2 knockdown increased STS-induced apoptosis.
- RCC2's protective effect against apoptosis was abolished by activated Rac1, confirming its role in Rac1-mediated apoptosis.
- RCC2 was overexpressed in 88.3% of primary lung cancers and 65.2% of ovarian cancers.
- Tumor cells with forced RCC2 expression exhibited altered sensitivity to common chemotherapeutic drugs.
Conclusions:
- RCC2 regulates apoptosis by inhibiting Rac1 signaling.
- Tumor RCC2 expression may serve as a predictive marker for chemotherapeutic response.
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