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Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a

William L Perry1, Robert L Shepard, Janardhan Sampath

  • 1Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana 46285, USA. bperry@lilly.com

Cancer Research
|August 3, 2005
PubMed

Insights

The splicing factor SPF45 (RBM17) confers significant drug resistance in ovarian cancer cells. Selective estrogen receptor modulators partially reverse this resistance, suggesting a link between SPF45, ERbeta, and drug sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • The splicing factor SPF45 (RBM17) is overexpressed in solid tumors.
  • SPF45 expression confers resistance to chemotherapy agents in HeLa cells.

Purpose of the Study:

  • To investigate the role of SPF45 in drug resistance in A2780 ovarian carcinoma cells.
  • To identify potential therapeutic strategies to overcome SPF45-mediated drug resistance.

Main Methods:

  • Stable transfection of A2780 cells with SPF45.
  • Cytotoxicity assays to determine drug resistance.
  • SPF45 knockdown using ribozymes.
  • Drug accumulation studies.
  • Treatment with selective estrogen receptor modulators (SERMs).
  • Quantitative PCR and coimmunoprecipitation to assess protein interactions.

Main Results:

  • SPF45 overexpression conferred 3- to 21-fold resistance to multiple chemotherapy drugs, including carboplatin, doxorubicin, and etoposide.
  • SPF45 knockdown sensitized cells to etoposide.
  • Drug resistance was not due to altered drug accumulation.
  • Tamoxifen and LY117018 partially reversed mitoxantrone resistance.
  • SPF45 physically interacts with ERbeta, which is expressed in A2780 cells.

Conclusions:

  • SPF45 plays a significant role in conferring chemoresistance in ovarian cancer cells.
  • SPF45-mediated drug resistance may involve interactions with ERbeta and affect ERbeta-regulated gene expression.
  • Targeting SPF45 or its interaction with ERbeta may offer new therapeutic avenues for overcoming drug resistance.

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