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Sec61β controls sensitivity to platinum-containing chemotherapeutic agents through modulation of the

Paolo B Abada1, Christopher A Larson, Gerald Manorek

  • 1Moores UCSD Cancer Center, La Jolla, CA 92093-0819, USA. pabada@ucsd.edu

Molecular Pharmacology
|June 20, 2012
PubMed

Insights

The Sec61β subunit significantly impacts ovarian cancer cell sensitivity to platinum-based chemotherapy drugs. Its knockdown confers resistance by altering copper transporter ATP7A expression and distribution.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Drug Discovery

Background:

  • The Sec61 protein translocon facilitates protein transport across lipid bilayers.
  • Cellular sensitivity to chemotherapeutic agents is crucial for treatment efficacy.
  • Platinum-based drugs are widely used in cancer therapy.

Purpose of the Study:

  • To investigate the role of the Sec61β subunit in modulating cellular sensitivity to platinum-based chemotherapeutic agents.
  • To elucidate the underlying molecular mechanisms by which Sec61β influences drug response.

Main Methods:

  • Constitutive knockdown of Sec61β expression in 2008 ovarian cancer cells.
  • Assessment of cellular resistance and accumulation of cisplatin (cDDP), carboplatin, and oxaliplatin.
  • Analysis of copper levels, uptake, and cytotoxicity.
  • Evaluation of copper transporter and chaperone gene expression (ATP7A, ATP7B, ATOX1, CTR1, CTR2).
  • Investigation of ATP7A's role in cDDP resistance and its cellular distribution.

Main Results:

  • Sec61β knockdown (KD) conferred significant resistance to cisplatin (8-fold), carboplatin (16.8-fold), and oxaliplatin (9-fold).
  • Sec61β KD reduced cellular cisplatin accumulation to 67% of parental cells.
  • ATP7A was overexpressed (2-3 fold) in Sec61β KD cells, while other copper-related genes remained unchanged.
  • Cells lacking ATP7A did not show increased cDDP resistance upon Sec61β KD.
  • Altered ATP7A cellular distribution was observed in Sec61β KD cells.

Conclusions:

  • Sec61β plays a critical role in modulating cellular sensitivity to platinum-based chemotherapeutic agents.
  • The mechanism involves Sec61β's influence on the expression and cellular distribution of the copper transporter ATP7A.
  • ATP7A appears to mediate platinum drug sequestration and cytotoxicity, thus impacting treatment outcomes.

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