Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents
Irina A Vasilevskaya1, Muthu Selvakumaran2, Lucia Cabal Hierro2
1Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. vasilevs@mail.med.upenn.edu.
Purpose:
We showed previously that in HT29 colon cancer cells, modulation of hypoxia-induced stress signaling affects oxaliplatin cytotoxicity. To further study the significance of hypoxia-induced signaling through JNK, we set out to investigate how modulation of kinase activities influences cellular responses of hypoxic colon cancer cells to cytotoxic drugs.
Experimental Design:
In a panel of cell lines, we investigated effects of pharmacologic and molecular inhibition of JNK on sensitivity to oxaliplatin, SN-38, and 5-FU. Combination studies for the drugs and JNK inhibitor CC-401 were carried out in vitro and in vivo.
Results:
Hypoxia-induced JNK activation was associated with resistance to oxaliplatin. CC-401 in combination with chemotherapy demonstrates synergism in colon cancer cell lines, although synergy is not always hypoxia specific. A more detailed analysis focused on HT29 and SW620 (responsive), and HCT116 (nonresponsive) lines. In HT29 and SW620 cells, CC-401 treatment results in greater DNA damage in the sensitive cells. In vivo, potentiation of bevacizumab, oxaliplatin, and the combination by JNK inhibition was confirmed in HT29-derived mouse xenografts, in which tumor growth delay was greater in the presence of CC-401. Finally, stable introduction of a dominant negative JNK1, but not JNK2, construct into HT29 cells rendered them more sensitive to oxaliplatin under hypoxia, suggesting differing input of JNK isoforms in cellular responses to chemotherapy.
Conclusions:
These findings demonstrate that signaling through JNK is a determinant of response to therapy in colon cancer models, and support the testing of JNK inhibition to sensitize colon tumors in the clinic.
Insights
Inhibition of hypoxia-induced JNK signaling enhances colon cancer cell sensitivity to chemotherapy drugs like oxaliplatin. This suggests JNK inhibitors could be a valuable addition to clinical cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Hypoxia-induced stress signaling pathways, particularly c-Jun N-terminal kinase (JNK), influence cancer cell response to chemotherapy.
- Previous studies indicated that modulating hypoxia-induced stress signaling affects oxaliplatin cytotoxicity in colon cancer cells.
Purpose of the Study:
- To investigate how modulating JNK kinase activity impacts the cellular response of hypoxic colon cancer cells to cytotoxic drugs.
- To determine the role of JNK signaling in mediating resistance or sensitivity to chemotherapy in colon cancer models.
Main Methods:
- Evaluated the effects of pharmacologic and molecular inhibition of JNK on colon cancer cell sensitivity to oxaliplatin, SN-38, and 5-FU.
- Conducted in vitro and in vivo combination studies using JNK inhibitor CC-401 with various chemotherapeutic agents.
- Utilized colon cancer cell lines (HT29, SW620, HCT116) and mouse xenograft models.
Main Results:
- Hypoxia-induced JNK activation correlated with resistance to oxaliplatin.
- The JNK inhibitor CC-401 demonstrated synergistic effects with chemotherapy in colon cancer cell lines, though not exclusively hypoxia-specific.
- CC-401 treatment increased DNA damage in oxaliplatin-sensitive HT29 and SW620 cells.
- In vivo studies confirmed that JNK inhibition potentiated chemotherapy and bevacizumab, leading to greater tumor growth delay in HT29 xenografts.
- Stable expression of dominant-negative JNK1 (but not JNK2) increased oxaliplatin sensitivity in hypoxic HT29 cells.
Conclusions:
- JNK signaling is a key determinant of therapeutic response in preclinical colon cancer models.
- Inhibition of JNK signaling can sensitize colon tumors to chemotherapy.
- These findings support the clinical investigation of JNK inhibitors for enhancing colon cancer treatment efficacy.
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