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DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer
Chi-Che Hsieh1,2, Ting-Wei Li1,3, Chun-Chun Li3
1National Institute of Cancer Research, National Health Research Institutes, Tainan, 704, Taiwan.
Abstract:
Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.
Insights
Dickkopf-1 (DKK1) protein drives resistance to oxaliplatin chemotherapy in colorectal cancer (CRC) by activating AKT signaling. Disrupting this interaction with a leucine zipper (LZ) protein restores oxaliplatin sensitivity in resistant CRC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Oxaliplatin is a key chemotherapy for colorectal cancer (CRC).
- Acquired resistance to oxaliplatin significantly limits its therapeutic efficacy in CRC patients.
- Mechanisms underlying oxaliplatin resistance in CRC require further elucidation.
Purpose of the Study:
- To investigate the role of Dickkopf-1 (DKK1) in mediating oxaliplatin resistance in colorectal cancer (CRC).
- To identify the molecular interaction responsible for DKK1-mediated chemoresistance.
- To explore therapeutic strategies targeting DKK1 signaling for overcoming oxaliplatin resistance.
Main Methods:
- Analysis of DKK1 expression in oxaliplatin-resistant (OR) CRC cell lines and patient tumors.
- Investigating the interaction between DKK1 and its receptor, cytoskeleton-associated protein 4 (CKAP4).
- Utilizing a leucine zipper (LZ) protein to disrupt DKK1-CKAP4 interaction and assess effects on oxaliplatin sensitivity in vitro and in vivo models.
Main Results:
- Upregulated DKK1 was observed in OR CRC cell lines and tumors ( >2-fold increase in ~50% of resistant tumors).
- DKK1 activates AKT signaling through CKAP4, modulating oxaliplatin response.
- The leucine zipper (LZ) domain of CKAP4 and CRD1 of DKK1 are critical for this interaction.
- Disruption of DKK1 signaling using the LZ protein enhanced oxaliplatin sensitivity in OR CRC cells and xenografts.
Conclusions:
- DKK1 acts as a chemoresistance factor in CRC by activating AKT signaling.
- Targeting the DKK1-CKAP4 interaction with LZ proteins presents a potential therapeutic strategy for oxaliplatin-resistant CRC.
- This study elucidates a novel mechanism of oxaliplatin resistance and offers an innovative intervention approach.
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