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Synthetic Lethality Induced by Loss of PKC δ and Mutated Ras

Tongbo Zhu1, Lihua Chen, Wei Du

  • 1Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Genes & Cancer
|October 30, 2010
PubMed

Insights

Loss of Protein Kinase C delta (PKC δ) triggers apoptosis in Ras-driven cancer cells by upregulating PKC α/β and JNK signaling. This highlights a synthetic lethal interaction crucial for cancer therapy development.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Synthetic lethality exists between oncogenic Ha-ras and Protein Kinase C (PKC) loss.
  • Previous work showed PKC α/β knockdown sensitizes Ras-aberrant cells to apoptosis via PKC δ upregulation.

Purpose of the Study:

  • To investigate the role of PKC δ loss in Ras-overexpressing cells.
  • To elucidate the apoptotic pathway triggered by PKC δ deficiency.

Main Methods:

  • Short hairpin RNA (shRNA) mediated knockdown of PKC δ.
  • Overexpression of JNK in NIH3T3/Hras and DU145 prostate cancer cells.
  • Immunoblotting for phosphorylated JNK and cleaved caspase 8.
  • JNK inhibition studies.

Main Results:

  • PKC δ knockdown induced apoptosis in JNK-overexpressing Ras-driven cells.
  • Apoptosis involved upregulation and RACK1-association of PKC α/β with JNK.
  • JNK phosphorylation and caspase 8 cleavage were observed.
  • JNK inhibition abrogated the apoptotic process.

Conclusions:

  • PKC δ loss triggers apoptosis in Ras-driven cancer cells, mediated by PKC α/β and JNK.
  • PKC α/β and δ have opposing roles in maintaining cell survival against oncogenic stress.
  • Targeting this synthetic lethal interaction could be a therapeutic strategy.
Keywords:
JNKPKCRACK1Rassynthetic lethality

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