Mitochondrial targeting domain of NOXA causes necrosis in apoptosis-resistant tumor cells
- 196 Downloads
The resistance of tumor cells to apoptosis-inducing anticancer agents is regarded as a major impediment for the treatment of cancer patients. This study aimed to examine the possibility whether a necrosis-inducing peptide containing the mitochondria-targeting domain (MTD) of NOXA kills tumor cells that are resistant to apoptosis-inducing anticancer agents. To examine this possibility, we established doxorubicin-resistant (Dox-Res) cells by treating CT26 cells with increasing amounts of doxorubicin. The apoptosis resistance of the Dox-Res CT26 cells was confirmed by measuring the cell viability and activation of caspases. We showed that the MTD-containing peptide fused to eight arginine residues (R8:MTD), a necrosis-inducing peptide, induced necrosis in the Dox-Res CT26 cells, together with a cytosolic calcium spike, reactive oxygen species production, and the release of high mobility group box 1 into the media. Moreover, we demonstrated the killing effect of R8:MTD in tumor tissues generated using the Dox-Res CT26 cells in a mouse model. Therefore, our results suggest that MTD-containing peptides may provide an alternative tool for the elimination of relapsed tumor cells that are not responsive to apoptosis-inducing anticancer agents.
KeywordsNecrosis Apoptosis Pro-necrotic peptide Mitochondrial targeting domain NOXA Apoptosis-resistant cell
This research was supported by the Ministry of Health and Welfare of the Korean government (Grant No. HI14C2025 to TH Kim), by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (Grant No. NRF-2013R1A1A2058254 to TH Kim), and by the Ministry of Science, ICT, and Future Planning (NRF-2014R1A2A1A11050442 to TH Kim).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
Statement on the welfare of animals
We followed the University Institutional Guidelines and Regulations of the Animal Care and Use Committee. All animal experiments were performed in accordance with the guidelines and regulations of the committee. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors. The Animal Ethics Committee at the Chosun University has approved the protocols for all animal experiments (Approval numbers: CIACUC2013-S0005 and CIACUC2015-S0019).