Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1

Benjamin Boyerinas, Sun Mi Park, Andrea E. Murmann, Katja Gwin, Anton G. Montag, Marion Zillhardt, You Jia Hua, Ernst Lengyel, Marcus E. Peter

Research output: Contribution to journalArticle

96 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1787-1797
Number of pages11
JournalInternational Journal of Cancer
Volume130
Issue number8
DOIs
StatePublished - Apr 15 2012

Fingerprint

Taxoids
Inosine Monophosphate
Multiple Drug Resistance
Ovarian Neoplasms
Paclitaxel
Carboplatin
Drug Delivery Systems
MicroRNAs
Drug Therapy
Down-Regulation
Small Untranslated RNA
Neoplasms
Proteins
Vinblastine
R Factors
Therapeutics
Microtubules
Up-Regulation
Recurrence
Messenger RNA

Keywords

  • IMP-1
  • let-7
  • Lin28
  • MDR1
  • Taxol

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1. / Boyerinas, Benjamin; Park, Sun Mi; Murmann, Andrea E.; Gwin, Katja; Montag, Anton G.; Zillhardt, Marion; Hua, You Jia; Lengyel, Ernst; Peter, Marcus E.

In: International Journal of Cancer, Vol. 130, No. 8, 15.04.2012, p. 1787-1797.

Research output: Contribution to journalArticle

Boyerinas, B, Park, SM, Murmann, AE, Gwin, K, Montag, AG, Zillhardt, M, Hua, YJ, Lengyel, E & Peter, ME 2012, 'Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1', International Journal of Cancer, vol. 130, no. 8, pp. 1787-1797. https://doi.org/10.1002/ijc.26190
Boyerinas, Benjamin ; Park, Sun Mi ; Murmann, Andrea E. ; Gwin, Katja ; Montag, Anton G. ; Zillhardt, Marion ; Hua, You Jia ; Lengyel, Ernst ; Peter, Marcus E. / Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1. In: International Journal of Cancer. 2012 ; Vol. 130, No. 8. pp. 1787-1797.
@article{fc5b140410344a28b0a49724f25eb278,
title = "Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1",
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.",
keywords = "IMP-1, let-7, Lin28, MDR1, Taxol",
author = "Benjamin Boyerinas and Park, {Sun Mi} and Murmann, {Andrea E.} and Katja Gwin and Montag, {Anton G.} and Marion Zillhardt and Hua, {You Jia} and Ernst Lengyel and Peter, {Marcus E.}",
year = "2012",
month = "4",
day = "15",
doi = "10.1002/ijc.26190",
language = "English (US)",
volume = "130",
pages = "1787--1797",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "8",

}

TY - JOUR

T1 - Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1

AU - Boyerinas, Benjamin

AU - Park, Sun Mi

AU - Murmann, Andrea E.

AU - Gwin, Katja

AU - Montag, Anton G.

AU - Zillhardt, Marion

AU - Hua, You Jia

AU - Lengyel, Ernst

AU - Peter, Marcus E.

PY - 2012/4/15

Y1 - 2012/4/15

N2 - 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.

AB - 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.

KW - IMP-1

KW - let-7

KW - Lin28

KW - MDR1

KW - Taxol

UR - http://www.scopus.com/inward/record.url?scp=84857503465&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857503465&partnerID=8YFLogxK

U2 - 10.1002/ijc.26190

DO - 10.1002/ijc.26190

M3 - Article

C2 - 21618519

AN - SCOPUS:84857503465

VL - 130

SP - 1787

EP - 1797

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 8

ER -