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Published on: February 2, 2021
JNK signaling is needed to tolerate chromosomal instability
Heidi W-S Wong1, Zeeshan Shaukat2, Jianbin Wang1
1Department of Genetics; University of Melbourne; Melbourne, VIC, Australia.
Abstract:
Chromosomal instability (CIN), as a common feature of tumors, represents a potential therapeutic target if ways can be found to specifically cause apoptosis in unstably dividing cells. We have previously shown that if signaling through the JNK pathway is reduced, apoptosis is triggered in models of chromosomal instability induced by loss of the spindle checkpoint. Here we identify components upstream and downstream of JNK that are able to mediate this effect, and test the involvement of p53 and DNA damage in causing apoptosis when JNK signaling is reduced in CIN cells. We show that cell cycle progression timing has a strong effect on the apoptosis seen when JNK signaling is reduced in genetically unstable cells: a shortened G 2 phase enhances the apoptosis, while lengthening G 2 rescues the JNK-deficient CIN cell death phenotype. Our findings suggest that chromosomal instability represents a significant stress to dividing cells, and that without JNK signaling, cells undergo apoptosis because they lack a timely and effective response to DNA damage.
Insights
Reducing JNK pathway signaling triggers apoptosis in cancer cells with chromosomal instability (CIN). Cell cycle timing, particularly G2 phase length, significantly impacts this cell death, suggesting therapeutic potential for CIN tumors.
Area of Science:
- Oncology
- Cell Biology
- Genetics
Background:
- Chromosomal instability (CIN) is a hallmark of cancer and a potential therapeutic target.
- Reduced JNK pathway signaling has been shown to induce apoptosis in CIN models.
- Understanding upstream/downstream mediators and p53/DNA damage involvement is crucial.
Purpose of the Study:
- Identify JNK pathway components mediating apoptosis in CIN cells.
- Investigate the roles of p53 and DNA damage in JNK-inhibited apoptosis.
- Determine the effect of cell cycle progression timing on apoptosis in CIN cells.
Main Methods:
- Investigated upstream and downstream components of the JNK pathway.
- Assessed the involvement of p53 and DNA damage.
- Manipulated cell cycle progression (G2 phase length) in CIN models.
- Analyzed apoptosis induction in response to JNK signaling reduction.
Main Results:
- Identified specific upstream and downstream JNK pathway components involved in apoptosis.
- Demonstrated that p53 and DNA damage contribute to apoptosis when JNK is inhibited.
- Showed that a shortened G2 phase enhances apoptosis in JNK-deficient CIN cells.
- Found that lengthening the G2 phase rescues CIN cell death.
Conclusions:
- Chromosomal instability imposes significant stress on dividing cells.
- Reduced JNK signaling impairs the timely DNA damage response in CIN cells, leading to apoptosis.
- Cell cycle timing is a critical factor influencing the efficacy of targeting JNK in CIN.
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