| Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel. | |
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MedLine Citation:
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PMID: 21761117 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Understanding the molecular events that lead to paclitaxel (TX) resistance is necessary to identify effective means to prevent chemoresistance. Previously, results from our lab revealed that secretory clusterin (CLU) form positively mediates TX response in ovarian cancer cells. Thus, we had interest to study the role of another non-secreted form (intracellular clusterin (i-CLU)) in chemo-response. Here, we provide evidences that i-CLU form localizes mainly in the nucleus and differentially expressed in the TX-responsive KF cells, versus TX-resistant, KF-TX, ovarian cancer cells and negatively regulate cellular chemo-response. I-CLU was cloned, by deleting the secretion-leading signaling peptide from full-length CLU cDNA, and transiently over-expressed in OVK-18 cells. Forced expression of truncated i-CLU was mainly detectable in the nuclei and significantly reduced cellular growth, accumulating cells in G1 phase which finally died through apoptosis. Importantly, compromised expression of i-CLU under an inducible promoter was tolerated and did not induce apoptosis but sensitized ovarian cancer cells to TX. We then demonstrated that this sensitization mechanism was cell cycle independent and relied on i-CLU/Ku70 binding probably due to controlling the free amount of Ku70 available for DNA repair in the nucleus. Results from CLU immunehistochemistry in ovarian tumor tissues verified the retardation of nuclear CLU staining in the recurrent tumor even though their primary counterparts showed nuclear CLU staining. Thus, the controversial data on CLU function in chemo-response/resistance may be explained by a shift in the pattern of CLU expression and intracellular localization as well when tumor acquires chemoresistance. |
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Authors:
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Mohamed Kamel Hassan; Hidemichi Watari; Lane Christenson; Saverio Bettuzzi; Noriaki Sakuragi |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-15 |
Journal Detail:
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Title: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine Volume: - ISSN: 1423-0380 ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-7-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8409922 Medline TA: Tumour Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Gynecology and Obstetrics, Graduate School of Medicine, Hokkaido University, Nishi Ku, Kita-15, Nishi-7, 060-8638, Sapporo, Japan, mohamedkamel24@yahoo.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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