Supplementary Tables S1-3, Figure S1. Table S1. Hypoxia increases signaling through JNK in colon cancer cell lines in a cell-specific manner Table S2. Hypoxia increases resistance to chemotherapy in colon cancer cell lines Table S3. Combination of the JNK inhibitor SP600125 with chemotherapy is synergistic in colon cancer cell lines Figure S1. Effects of oxaliplatin and SN-38 on JNK pathway in oxic conditions.
ARTICLE ABSTRACT
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. Clin Cancer Res; 21(18); 4143–52. ©2015 AACR.
