Abstract |
Ovarian cancer patients frequently develop resistance to chemotherapy regiments using Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol-based therapy is multidrug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let-7 family of miRNAs are downregulated in many human cancers, and low let-7 expression has been correlated with resistance to microtubule targeting drugs ( Taxanes), although little is known that would explain this activity. We now provide evidence that, although let-7 is not a universal sensitizer of cancer cells to Taxanes, it affects acquired resistance of cells to this class of drugs by targeting IMP-1, resulting in destabilization of the mRNA of MDR1. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin, a non-MDR1 substrate. This effect could be reversed by reintroducing IMP-1 into let-7g high/MDR1 low cells causing MDR1 to again become stabilized. Consistently, many relapsed ovarian cancer patients tested before and after chemotherapy were found to downregulate let-7 and to co-upregulate IMP-1 and MDR1, and the increase in the expression levels of both proteins after chemotherapy negatively correlated with disease-free time before recurrence. Our data point at IMP-1 and MDR1 as indicators for response to therapy, and at IMP-1 as a novel therapeutic target for overcoming multidrug resistance of ovarian cancer.
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Authors | Benjamin Boyerinas, Sun-Mi Park, Andrea E Murmann, Katja Gwin, Anton G Montag, Marion Zillhardt, You-Jia Hua, Ernst Lengyel, Marcus E Peter |
Journal | International journal of cancer
(Int J Cancer)
Vol. 130
Issue 8
Pg. 1787-97
(Apr 15 2012)
ISSN: 1097-0215 [Electronic] United States |
PMID | 21618519
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 UICC. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- DNA-Binding Proteins
- IGF2BP1 protein, human
- LIN28B protein, human
- MicroRNAs
- RNA, Messenger
- RNA-Binding Proteins
- Taxoids
- mirnlet7 microRNA, human
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(genetics, metabolism)
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Blotting, Western
- Cell Line, Tumor
- Cell Survival
(drug effects, genetics)
- DNA-Binding Proteins
(genetics, metabolism)
- Disease-Free Survival
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
(drug effects, genetics)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- HEK293 Cells
- HeLa Cells
- Humans
- Immunohistochemistry
- In Situ Hybridization
- MicroRNAs
(genetics)
- Ovarian Neoplasms
(drug therapy, genetics, pathology)
- RNA Interference
- RNA, Messenger
(genetics, metabolism)
- RNA-Binding Proteins
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Taxoids
(pharmacology, therapeutic use)
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