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Published on: December 21, 2011
RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels
Nicholas Yagoda1, Moritz von Rechenberg, Elma Zaganjor
1Department of Biological Sciences, Fairchild Center, 1212 Amsterdam Avenue, MC 2406, New York, New York 10027, USA.
Abstract:
Therapeutics that discriminate between the genetic makeup of normal cells and tumour cells are valuable for treating and understanding cancer. Small molecules with oncogene-selective lethality may reveal novel functions of oncoproteins and enable the creation of more selective drugs. Here we describe the mechanism of action of the selective anti-tumour agent erastin, involving the RAS-RAF-MEK signalling pathway functioning in cell proliferation, differentiation and survival. Erastin exhibits greater lethality in human tumour cells harbouring mutations in the oncogenes HRAS, KRAS or BRAF. Using affinity purification and mass spectrometry, we discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs)--a novel target for anti-cancer drugs. We show that erastin treatment of cells harbouring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin, implicating these two VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, we found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabelled analogue and a filter-binding assay, we show that erastin binds directly to VDAC2. These results demonstrate that ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway.
Insights
Erastin selectively kills cancer cells with RAS-RAF-MEK pathway mutations by targeting mitochondrial VDAC proteins, inducing oxidative stress and non-apoptotic cell death. This reveals VDACs as novel anti-cancer drug targets.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Targeted cancer therapies require agents that discriminate between normal and tumor cells.
- Oncogene-selective lethality offers a strategy for developing more effective and less toxic anti-cancer drugs.
- The RAS-RAF-MEK signaling pathway is crucial for cell proliferation, differentiation, and survival, and is frequently mutated in cancers.
Purpose of the Study:
- To elucidate the mechanism of action of the selective anti-tumor agent erastin.
- To identify novel molecular targets for cancer therapeutics.
- To investigate the role of the RAS-RAF-MEK pathway in erastin's anti-cancer activity.
Main Methods:
- Affinity purification and mass spectrometry to identify erastin's binding partners.
- Cell viability assays to assess erastin's lethality in cancer cells with specific oncogenic mutations.
- RNA interference to investigate the role of VDAC isoforms.
- Mitochondrial permeability assays.
- Filter-binding assays with radiolabeled erastin.
Main Results:
- Erastin exhibits selective lethality towards human tumor cells with HRAS, KRAS, or BRAF mutations.
- Erastin targets mitochondrial voltage-dependent anion channels (VDACs).
- Erastin induces oxidative species and non-apoptotic cell death in oncogenic RAS-expressing cells.
- VDAC2 and VDAC3 knockdown confers resistance to erastin.
- Erastin alters outer mitochondrial membrane permeability and directly binds to VDAC2.
Conclusions:
- Erastin functions by targeting VDAC proteins, a novel mechanism for anti-cancer drugs.
- Ligands targeting VDAC proteins can induce selective non-apoptotic cell death in tumors with activating mutations in the RAS-RAF-MEK pathway.
- This study identifies VDACs as promising targets for developing novel, selective cancer therapeutics.
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