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Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair
Jingyi Tang1, Patrick J Casey1,2, Mei Wang3,4
1Duke-NUS Medical School, Program in Cancer and Stem Cell, Singapore, Singapore.
Abstract:
DNA damage is a double-edged sword for cancer cells. On the one hand, DNA damage-induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Understanding the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that isoprenylcysteine carboxylmethyltransferase (ICMT), a posttranslational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition transforms the cancer cells into a "BRCA-like" state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage-inducing agents.
Insights
Isoprenylcysteine carboxylmethyltransferase (ICMT) is crucial for cancer cell DNA repair. Inhibiting ICMT triggers DNA damage, cell cycle arrest, and apoptosis, sensitizing cancer cells to therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- DNA damage is a critical factor in cancer development and progression.
- Understanding DNA damage repair mechanisms is essential for developing effective cancer therapies.
- Key regulators of DNA repair pathways offer potential therapeutic targets.
Purpose of the Study:
- To investigate the role of isoprenylcysteine carboxylmethyltransferase (ICMT) in DNA damage repair in breast cancer cells.
- To elucidate the molecular mechanisms by which ICMT influences DNA damage response.
- To evaluate the therapeutic potential of ICMT inhibition in sensitizing cancer cells to DNA-damaging agents.
Main Methods:
- Utilized multiple breast cancer cell lines.
- Investigated the effect of ICMT suppression on MAPK signaling pathway activity.
- Assessed the expression of key DNA damage repair proteins.
- Examined cell cycle progression and apoptosis induction.
- Studied cancer cell behavior under anchorage-independent conditions and in vivo.
- Evaluated the impact of ICMT inhibition on sensitivity to PARP inhibitors and DNA damage-inducing agents.
Main Results:
- ICMT suppression significantly reduced MAPK signaling activity.
- Reduced MAPK signaling led to decreased expression of DNA damage repair proteins.
- Accumulation of DNA damage resulted in cell cycle arrest and apoptosis in breast cancer cells.
- These effects were more pronounced in cells grown under anchorage-independent conditions and in vivo.
- ICMT inhibition induced a "BRCA-like" state in cancer cells.
- ICMT inhibition sensitized cancer cells to PARP inhibitors and other DNA damage-inducing agents.
Conclusions:
- ICMT plays a significant role in maintaining DNA damage repair capacity in breast cancer cells.
- ICMT inhibition disrupts DNA repair by downregulating MAPK signaling, leading to synthetic lethality.
- Targeting ICMT represents a promising strategy to enhance the efficacy of existing DNA damage-based cancer therapies.
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