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.


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


  • 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