dTMP imbalance through thymidylate 5'-phosphohydrolase activity induces apoptosis in triple-negative breast cancers
Dae-Ho Kim1,2,3, Jin-Sook Kim1, Chang-Soo Mok1,4
1Research Center, BPgene Co, Ltd, Seoul, 03127, Republic of Korea.
Abstract:
Immunotherapy has a number of advantages over traditional anti-tumor therapy but can cause severe adverse reactions due to an overactive immune system. In contrast, a novel metabolic treatment approach can induce metabolic vulnerability through multiple cancer cell targets. Here, we show a therapeutic effect by inducing nucleotide imbalance and apoptosis in triple negative breast cancer cells (TNBC), by treating with cytosolic thymidylate 5'-phosphohydrolase (CT). We show that a sustained consumption of dTMP by CT could induce dNTP imbalance, leading to apoptosis as tricarboxylic acid cycle intermediates were depleted to mitigate this imbalance. These cytotoxic effects appeared to be different, depending on substrate specificity of the 5' nucleotide or metabolic dependency of the cancer cell lines. Using representative TNBC cell lines, we reveal how the TNBC cells were affected by CT-transfection through extracellular acidification rate (ECAR)/oxygen consumption rate (OCR) analysis and differential transcription/expression levels. We suggest a novel approach for treating refractory TNBC by an mRNA drug that can exploit metabolic dependencies to exacerbate cell metabolic vulnerability.
Insights
This study introduces a novel metabolic therapy for triple-negative breast cancer (TNBC). By targeting nucleotide metabolism with cytosolic thymidylate 5'-phosphohydrolase (CT), it induces cancer cell death, offering a new treatment avenue.
Area of Science:
- Oncology
- Metabolic pathways
- Cancer cell biology
Background:
- Immunotherapy for cancer can cause severe side effects due to immune overactivation.
- Metabolic therapies offer a novel approach to target cancer cells by inducing metabolic vulnerability.
- Triple-negative breast cancer (TNBC) remains a challenging subtype with limited treatment options.
Purpose of the Study:
- To investigate the therapeutic potential of cytosolic thymidylate 5 '-phosphohydrolase (CT) in treating triple-negative breast cancer (TNBC).
- To elucidate the mechanism by which CT induces cancer cell death through metabolic manipulation.
- To explore the development of an mRNA drug for refractory TNBC targeting metabolic vulnerabilities.
Main Methods:
- Treatment of TNBC cell lines with cytosolic thymidylate 5 '-phosphohydrolase (CT).
- Analysis of nucleotide imbalance and apoptosis induction.
- Measurement of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR).
- Differential gene transcription and expression analysis.
Main Results:
- CT treatment led to sustained consumption of dTMP, inducing deoxynucleotide triphosphate (dNTP) imbalance and apoptosis in TNBC cells.
- Tricarboxylic acid cycle intermediates were depleted to mitigate the dNTP imbalance, contributing to cytotoxicity.
- Cytotoxic effects varied based on nucleotide specificity and cancer cell line metabolic dependencies.
- CT-transfection altered cellular metabolism and gene expression in TNBC cells.
Conclusions:
- Targeting nucleotide metabolism with CT represents a promising therapeutic strategy for TNBC.
- Exploiting cancer cell metabolic dependencies can exacerbate vulnerability and induce cell death.
- An mRNA drug delivering CT could offer a novel treatment for refractory TNBC by leveraging these metabolic vulnerabilities.
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