miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Xiaolan Zhu; Yuefeng Li; Chanjuan Xie; Xinming Yin; Yueqin Liu; Yuan Cao; Yue Fang; Xin Lin; Yao Xu; Wenlin Xu; Huiling Shen; Jian Wen

doi:10.1002/ijc.28774

miR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6

Int J Cancer. 2014 Sep 15;135(6):1286-96. doi: 10.1002/ijc.28774. Epub 2014 Apr 28.

Authors

Xiaolan Zhu¹, Yuefeng Li, Chanjuan Xie, Xinming Yin, Yueqin Liu, Yuan Cao, Yue Fang, Xin Lin, Yao Xu, Wenlin Xu, Huiling Shen, Jian Wen

Affiliation

¹ The Fourth Affiliated Hospital of Jiangsu University, Department of gynecology, Zhenjiang, Jiangsu, China; Jiangsu University, school of medical science and laborratory medicine, Zhenjiang, Jiangsu, China.

PMID: 24510775
DOI: 10.1002/ijc.28774

Abstract

Multidrug resistance (MDR) remains a major obstacle to effective chemotherapy treatment in ovarian cancer. In our study, paclitaxel-resistant ovarian cancer patients and cell lines had decreased miR-145 levels and expressed high levels of Sp1 and Cdk6. Introducing miR-145 into SKOV3/PTX and A2780/PTX cells led to a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. These changes resulted in increased accumulation of antineoplastic drugs and G1 cell cycle arrest, which rendered the cells more sensitive to paclitaxel in vitro and in vivo. These effects could be reversed by reintroducing Sp1 or Cdk6 into cells expressing high levels of miR-145, resulting in restoration of P-gp and pRb levels. Furthermore, we confirmed that both Cdk6 and Sp1 are targets of miR-145. Intriguingly, demethylation with 5-aza-dC led to reactivation of miR-145 expression in drug-resistant ovarian cancer cell lines, which also resulted in increased sensitivity to paclitaxel. Collectively, these findings begin to elucidate the role of miR-145 as an important regulator of chemoresistance in ovarian cancer by controlling both Cdk6 and Sp1.

Keywords: Cdk6; P-gp; Sp1; miR-145; pRb.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Animals
Antineoplastic Agents, Phytogenic / pharmacokinetics
Antineoplastic Agents, Phytogenic / pharmacology
Cell Cycle Checkpoints / drug effects
Cell Cycle Checkpoints / genetics
Cell Line, Tumor
Cyclin-Dependent Kinase 6 / biosynthesis
Cyclin-Dependent Kinase 6 / genetics
Cyclin-Dependent Kinase 6 / metabolism*
Drug Resistance, Neoplasm
Female
Humans
MCF-7 Cells
Mice
Mice, Inbred BALB C
MicroRNAs / administration & dosage*
MicroRNAs / genetics
MicroRNAs / metabolism*
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / therapy*
Paclitaxel / pharmacokinetics
Paclitaxel / pharmacology*
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Retinoblastoma Protein / biosynthesis
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Sp1 Transcription Factor / biosynthesis
Sp1 Transcription Factor / genetics
Sp1 Transcription Factor / metabolism*
Transfection
Xenograft Model Antitumor Assays

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents, Phytogenic
MIRN145 microRNA, human
MicroRNAs
RNA, Small Interfering
Retinoblastoma Protein
Sp1 Transcription Factor
CDK6 protein, human
Cyclin-Dependent Kinase 6
Paclitaxel