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Published on: May 14, 2016
Tumor cell dependence on Ran-GTP-directed mitosis
Fang Xia1, Connie W Lee, Dario C Altieri
1Department of Cancer Biology, Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Abstract:
Deregulated cell division is a hallmark of cancer, but whether tumor cells become dependent on specific mitotic mechanisms is not known. Here, we show that the small GTPase Ran, a regulator of mitotic spindle formation, is differentially overexpressed in human cancer as compared with normal tissues, in vivo. Acute silencing of Ran in various tumor cell types causes aberrant mitotic spindle formation, mitochondrial dysfunction, and apoptosis. This pathway does not require p53, Bax, or Smac, but is controlled by survivin as a novel Ran target in cancer. Conversely, loss of Ran in normal cells is well tolerated and does not result in mitotic defects or loss of cell viability. Therefore, tumor cells can become dependent on Ran signaling for cell division, and targeting this pathway may provide a novel and selective anticancer strategy.
Insights
Cancer cells rely on the small GTPase Ran for cell division. Silencing Ran causes cancer cell death without harming normal cells, suggesting Ran as a potential anticancer target.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Deregulated cell division is a key characteristic of cancer.
- The specific mitotic mechanisms tumor cells depend on remain largely unknown.
- The role of the small GTPase Ran in cancer cell division requires further investigation.
Purpose of the Study:
- To investigate the role of the small GTPase Ran in cancer cell division.
- To determine if tumor cells become dependent on Ran signaling for mitosis.
- To explore the potential of targeting Ran as a selective anticancer strategy.
Main Methods:
- Differential expression analysis of Ran in human cancer versus normal tissues.
- Acute silencing of Ran in various tumor cell types.
- Assessment of mitotic spindle formation, mitochondrial function, and apoptosis.
- Investigation of the involvement of p53, Bax, Smac, and survivin.
Main Results:
- Ran is differentially overexpressed in human cancers compared to normal tissues.
- Acute Ran silencing in tumor cells leads to aberrant mitosis, mitochondrial dysfunction, and apoptosis.
- This Ran-dependent pathway is independent of p53, Bax, and Smac.
- Survivin is identified as a novel Ran target in cancer cells.
- Normal cells tolerate loss of Ran without adverse effects on viability or mitosis.
Conclusions:
- Tumor cells exhibit a dependency on Ran signaling for successful cell division.
- Targeting the Ran pathway presents a promising strategy for developing novel and selective cancer therapies.
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