JNK1 Inhibition Attenuates Hypoxia-Induced Autophagy and Sensitizes to Chemotherapy
Irina A Vasilevskaya1, Muthu Selvakumaran2, David Roberts2
1Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. vasilevs@mail.med.upenn.edu.
Unlabelled:
Inhibition of hypoxia-induced stress signaling through JNK potentiates the effects of oxaliplatin. The JNK pathway plays a role in both autophagy and apoptosis; therefore, it was determined how much of the effect of JNK inhibition on oxaliplatin sensitivity is dependent on its effect on autophagy. We studied the impact of JNK isoform downregulation in the HT29 colon adenocarcinoma cell line on hypoxia- and oxaliplatin-induced responses. Electron microscopic analyses demonstrated that both oxaliplatin- and hypoxia-induced formations of autophagosomes were reduced significantly in HT29 cells treated with the JNK inhibitor SP600125. The role of specific JNK isoforms was defined using HT29-derived cell lines stably expressing dominant-negative constructs for JNK1 and JNK2 (HTJ1.3 and HTJ2.2, respectively). These cell lines demonstrated that functional JNK1 is required for hypoxia-induced autophagy and that JNK2 does not substitute for it. Inhibition of autophagy in HTJ1.3 cells also coincided with enhancement of intrinsic apoptosis. Analysis of Bcl2-family proteins revealed hyperphosphorylation of Bcl-XL in the HTJ1.3 cell line, but this did not lead to the expected dissociation from Beclin 1. Consistent with this, knockdown of Bcl-XL in HT29 cells did not significantly affect the induction of autophagy, but abrogated hypoxic resistance to oxaliplatin due to the faster and more robust activation of apoptosis.
Implications:
These data suggest that balance between autophagy and apoptosis is shifted toward apoptosis by downregulation of JNK1, contributing to oxaliplatin sensitization. These findings further support the investigation of JNK inhibition in colorectal cancer treatment. Mol Cancer Res; 14(8); 753-63. ©2016 AACR.
Insights
Inhibiting JNK1 in colorectal cancer cells enhances oxaliplatin effectiveness by shifting the balance from autophagy to apoptosis. This suggests JNK inhibition is a promising strategy for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Stress Response
Background:
- The c-Jun N-terminal kinase (JNK) pathway is implicated in cellular responses to stress, including hypoxia and chemotherapy.
- JNK signaling influences both autophagy and apoptosis, crucial processes in cancer cell survival and death.
- Oxaliplatin is a key chemotherapeutic agent for colorectal cancer, but its efficacy can be limited by cellular resistance mechanisms.
Purpose of the Study:
- To investigate the role of JNK isoforms in mediating cellular responses to hypoxia and oxaliplatin in colorectal cancer.
- To determine the extent to which JNK inhibition's potentiation of oxaliplatin effects is dependent on its modulation of autophagy.
- To explore the therapeutic potential of targeting JNK in combination with oxaliplatin for colorectal cancer treatment.
Main Methods:
- Utilized HT29 colon adenocarcinoma cells and derived cell lines with stable dominant-negative constructs for JNK1 and JNK2.
- Employed electron microscopy to analyze autophagosome formation under hypoxia and oxaliplatin treatment with or without JNK inhibition (SP600125).
- Assessed apoptosis and Bcl-2 family protein expression, including Bcl-XL and Beclin 1 interactions.
Main Results:
- JNK inhibition (SP600125) significantly reduced hypoxia- and oxaliplatin-induced autophagosome formation.
- Functional JNK1, but not JNK2, was essential for hypoxia-induced autophagy.
- Inhibition of autophagy via JNK1 downregulation enhanced intrinsic apoptosis and sensitized cells to oxaliplatin, even with Bcl-XL modulation.
Conclusions:
- Downregulation of JNK1 shifts the balance between autophagy and apoptosis towards apoptosis, thereby sensitizing colorectal cancer cells to oxaliplatin.
- Targeting JNK, particularly JNK1, represents a viable therapeutic strategy to enhance oxaliplatin efficacy in colorectal cancer treatment.
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