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Mortalin sensitizes human cancer cells to MKT-077-induced senescence
Custer C Deocaris1, Nashi Widodo, Bhupal G Shrestha
1National Institute of Advanced Industrial Science and Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305 8562, Japan.
Abstract:
Mortalin is a chaperone protein that functions in many cellular processes such as mitochondrial biogenesis, intracellular trafficking, cell proliferation and signaling. Its upregulation in many human cancers makes it a candidate target for therapeutic intervention by small molecule drugs. In continuation to our earlier studies showing mortalin as a cellular target of MKT-077, a mitochondrion-seeking delocalized cationic dye that causes selective death of cancer cells, in this work, we report that MKT-077 binds to the nucleotide-binding domain of mortalin, causes tertiary structural changes in the protein, inactivates its chaperone function, and induces senescence in human tumor cell lines. Interestingly, in tumor cells with elevated level of mortalin expression, fairly low drug doses were sufficient to induce senescence. Guided by molecular screening for mortalin in tumor cells, our results led to the idea that working at low doses of the drug could be an alternative senescence-inducing cancer therapeutic strategy that could, in theory, avoid renal toxicities responsible for the abortion of MKT-077 clinical trials. Our work may likely translate to a re-appraisal of the therapeutic benefits of low doses of several classes of anti-tumor drugs, even of those that had been discontinued due to adverse effects.
Insights
The small molecule drug MKT-077 targets mortalin, a protein upregulated in cancer. Low doses of MKT-077 induce cancer cell senescence by altering mortalin structure and function, offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Mortalin is a chaperone protein crucial for cellular functions.
- Its overexpression in human cancers presents a therapeutic target for small molecule drugs.
- MKT-077 is a mitochondrion-seeking dye previously identified as a mortalin target.
Purpose of the Study:
- To investigate the mechanism of MKT-077 action on mortalin.
- To explore the potential of low-dose MKT-077 for inducing cancer cell senescence.
- To assess the therapeutic implications of targeting mortalin with low-dose MKT-077.
Main Methods:
- Molecular screening of mortalin in tumor cells.
- Biochemical assays to determine MKT-077 binding site on mortalin.
- Analysis of MKT-077-induced structural and functional changes in mortalin.
- Cellular assays to evaluate senescence induction in human tumor cell lines.
Main Results:
- MKT-077 binds to the nucleotide-binding domain of mortalin.
- This binding induces structural changes, inactivates mortalin's chaperone activity.
- Low doses of MKT-077 effectively induce senescence in human tumor cells, particularly those with high mortalin expression.
- This suggests a potential strategy to avoid renal toxicities observed in previous MKT-077 trials.
Conclusions:
- MKT-077's interaction with mortalin offers a novel mechanism for cancer therapy.
- Low-dose MKT-077 can induce cancer cell senescence, potentially circumventing adverse effects.
- This approach may lead to a re-evaluation of low-dose anti-tumor drug therapies.
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