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Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional

Zuzanna Baranski1, Tijmen H Booij1, Anne-Marie Cleton-Jansen2

  • 1Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands.

The Journal of Pathology
|March 11, 2015
PubMed

Insights

Aven protein promotes osteosarcoma (bone cancer) metastasis and resistance to chemotherapy. Inhibiting Chk1, a key protein in the Aven pathway, sensitizes osteosarcoma cells to standard treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • High-grade osteosarcoma is a common bone cancer in young individuals.
  • Aven, an adaptor protein, is linked to anti-apoptotic signaling and cancer progression.
  • Osteosarcoma presents treatment challenges due to chemotherapy resistance.

Purpose of the Study:

  • To investigate the role of Aven in osteosarcoma metastasis and chemoresistance.
  • To explore the Aven-ATR-Chk1 signaling pathway in osteosarcoma.
  • To evaluate Chk1 inhibition as a strategy to sensitize osteosarcoma to chemotherapy.

Main Methods:

  • Assessed Aven expression in osteosarcoma patient samples and metastases.
  • Utilized Aven silencing in osteosarcoma cells to study cell-cycle arrest and DNA damage response.
  • Examined the effects of pharmacological Chk1/Chk2 inhibitors in combination with chemotherapy in 2D and 3D cell cultures.

Main Results:

  • Aven expression inversely correlated with metastasis-free survival and was elevated in metastases.
  • Aven depletion caused G2 cell-cycle arrest and abolished ATR-Chk1 signaling in response to chemotherapy.
  • Pharmacological Chk1 or Chk1/Chk2 inhibition synergized with chemotherapy in both 2D and 3D osteosarcoma cultures.

Conclusions:

  • Aven plays a critical role in ATR-Chk1 signaling in osteosarcoma.
  • Targeting Chk1 is a promising strategy to overcome chemotherapy resistance in osteosarcoma.
  • This study identifies Aven and Chk1 as potential therapeutic targets for osteosarcoma treatment.
Keywords:
3D cell cultureAvenChk1 inhibitorsdoxorubicinosteosarcoma

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