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Cyclin G1 regulates the outcome of taxane-induced mitotic checkpoint arrest.

Russell P, Hennessy BT, Li J, Carey MS, Bast RC, Freeman T, Venkitaraman AR - Oncogene (2011)

Bottom Line: However, the mechanisms that determine these outcomes remain unclear.Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds.Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: University of Cambridge, Department of Oncology and The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.

ABSTRACT
Anti-mitotic chemotherapeutic agents such as taxanes activate the spindle assembly checkpoint (SAC) to arrest anaphase onset, but taxane-exposed cells eventually undergo slippage to exit mitosis. The therapeutic efficacy of taxanes depends on whether slippage after SAC arrest culminates in continued cell survival, or in death by apoptosis. However, the mechanisms that determine these outcomes remain unclear. Here, we identify a novel role for cyclin G1 (CCNG1), an atypical cyclin. Increased CCNG1 expression accompanies paclitaxel-induced, SAC-mediated mitotic arrest, independent of p53 integrity or signaling through the SAC component, BUBR1. CCNG1 overexpression promotes cell survival after paclitaxel exposure. Conversely, CCNG1 depletion by RNA interference delays slippage and enhances paclitaxel-induced apoptosis. Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds. Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.

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Related in: MedlinePlus

CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer. Kaplan–Meier survival plots show the post-surgical survival in patients with CCNG1 copy number ⩽2 (n=66) compared with that in patients with CCNG1 copy number >2 (n=34). The plots demonstrate a statistically significant difference in patient survival (P=0.023, Wilcoxon–Gehan test).
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fig6: CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer. Kaplan–Meier survival plots show the post-surgical survival in patients with CCNG1 copy number ⩽2 (n=66) compared with that in patients with CCNG1 copy number >2 (n=34). The plots demonstrate a statistically significant difference in patient survival (P=0.023, Wilcoxon–Gehan test).

Mentions: These observations prompted us to test whether CCNG1 expression might serve as a prognostic marker for patient survival in ovarian cancer, a setting in which taxanes are frequently used in adjuvant chemotherapy (Markman, 2008; Hennessy et al., 2009). We examined snap-frozen ovarian cancer tissue samples collected at debulking surgery from 100 patients, all of which were collected before treatment, for CCNG1 copy number, and the expression of CCNG1 RNA. No association was found between CCNG1 mRNA expression levels and patient survival. The lack of such an association in pre-treatment tissue samples is not unexpected, as elevated CCNG1 expression appears to be transiently induced during drug-induced mitotic arrest. Therefore, CCNG1 gene copy number was assessed by a previously reported method that is likelihood-based and explicitly takes into account changes in the total genome size, and contamination of the cancer samples with non-cancerous cells (Abkevich et al., 2010). The method is capable of detecting regions with deletions and amplifications as well as estimating actual gene copy numbers in these regions. In contrast to mRNA expression, there was a statistically significant association between CCNG1 gene copy number and patient survival. Kaplan–Meier survival plots (Figure 6) demonstrate that post-surgical survival in patients with CCNG1 copy number ⩽2 (n=66) was significantly prolonged (P=0.023) compared with that in patients with CCNG1 copy number >2 (n=34). This significance holds in multivariate Cox models after accounting for the residual size of the ovarian tumor after surgery as well as the tumor stage (P=0.009). Collectively, these data suggest that CCNG1 gene copy number is an independent marker of post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds.


Cyclin G1 regulates the outcome of taxane-induced mitotic checkpoint arrest.

Russell P, Hennessy BT, Li J, Carey MS, Bast RC, Freeman T, Venkitaraman AR - Oncogene (2011)

CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer. Kaplan–Meier survival plots show the post-surgical survival in patients with CCNG1 copy number ⩽2 (n=66) compared with that in patients with CCNG1 copy number >2 (n=34). The plots demonstrate a statistically significant difference in patient survival (P=0.023, Wilcoxon–Gehan test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351588&req=5

fig6: CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer. Kaplan–Meier survival plots show the post-surgical survival in patients with CCNG1 copy number ⩽2 (n=66) compared with that in patients with CCNG1 copy number >2 (n=34). The plots demonstrate a statistically significant difference in patient survival (P=0.023, Wilcoxon–Gehan test).
Mentions: These observations prompted us to test whether CCNG1 expression might serve as a prognostic marker for patient survival in ovarian cancer, a setting in which taxanes are frequently used in adjuvant chemotherapy (Markman, 2008; Hennessy et al., 2009). We examined snap-frozen ovarian cancer tissue samples collected at debulking surgery from 100 patients, all of which were collected before treatment, for CCNG1 copy number, and the expression of CCNG1 RNA. No association was found between CCNG1 mRNA expression levels and patient survival. The lack of such an association in pre-treatment tissue samples is not unexpected, as elevated CCNG1 expression appears to be transiently induced during drug-induced mitotic arrest. Therefore, CCNG1 gene copy number was assessed by a previously reported method that is likelihood-based and explicitly takes into account changes in the total genome size, and contamination of the cancer samples with non-cancerous cells (Abkevich et al., 2010). The method is capable of detecting regions with deletions and amplifications as well as estimating actual gene copy numbers in these regions. In contrast to mRNA expression, there was a statistically significant association between CCNG1 gene copy number and patient survival. Kaplan–Meier survival plots (Figure 6) demonstrate that post-surgical survival in patients with CCNG1 copy number ⩽2 (n=66) was significantly prolonged (P=0.023) compared with that in patients with CCNG1 copy number >2 (n=34). This significance holds in multivariate Cox models after accounting for the residual size of the ovarian tumor after surgery as well as the tumor stage (P=0.009). Collectively, these data suggest that CCNG1 gene copy number is an independent marker of post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds.

Bottom Line: However, the mechanisms that determine these outcomes remain unclear.Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds.Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: University of Cambridge, Department of Oncology and The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.

ABSTRACT
Anti-mitotic chemotherapeutic agents such as taxanes activate the spindle assembly checkpoint (SAC) to arrest anaphase onset, but taxane-exposed cells eventually undergo slippage to exit mitosis. The therapeutic efficacy of taxanes depends on whether slippage after SAC arrest culminates in continued cell survival, or in death by apoptosis. However, the mechanisms that determine these outcomes remain unclear. Here, we identify a novel role for cyclin G1 (CCNG1), an atypical cyclin. Increased CCNG1 expression accompanies paclitaxel-induced, SAC-mediated mitotic arrest, independent of p53 integrity or signaling through the SAC component, BUBR1. CCNG1 overexpression promotes cell survival after paclitaxel exposure. Conversely, CCNG1 depletion by RNA interference delays slippage and enhances paclitaxel-induced apoptosis. Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds. Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.

Show MeSH
Related in: MedlinePlus