Inhibiting autophagy with chloroquine enhances the anti-tumor effect of high-LET carbon ions via ER stress-related apoptosis
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Energetic carbon ions (CI) offer great advantages over conventional radiations such as X- or γ-rays in cancer radiotherapy. High linear energy transfer (LET) CI can induce both endoplasmic reticulum (ER) stress and autophagy in tumor cells under certain circumstances. The molecular connection between ER stress and autophagy in tumor exposed to high-LET radiation and how these two pathways influence the therapeutic effect against tumor remain poorly understood. In this work, we studied the impact of autophagy and apoptosis induced by ER stress following high-LET CI radiation on the radiosensitivity of S180 cells both in vitro and in vivo. In the in vitro experiment, X-rays were also used as a reference radiation. Our results documented that the combination of CI radiation with chloroquine (CQ), a special autophagy inhibitor, produced more pronounced proliferation suppression in S180 cells and xenograft tumors. Co-treatment with CI radiation and CQ could block autophagy through the IRE1/JNK/Beclin-1 axis and enhance apoptotic cell death via the activation of C/EBP homologous protein (CHOP) by the IRE1 pathway rather than PERK in vitro and in vivo. Thus, our study indicates that inhibiting autophagy might be a promising therapeutic strategy in CI radiotherapy via aggravating the ER stress-related apoptosis.
KeywordsHigh-LET radiation Autophagy Chloroquine ER stress Apoptosis CHOP
This work was jointly supported by the Key Project of the National Natural Science Foundation of China (Grant No. U1232207), the National Key Technology Support Program of the Ministry of Science and Technology of China (Grant No. 2015BAI01B11), the National Key Research and Development Program of the Ministry of Science and Technology of China (Grant No. 2016YFC0904602) and the National Natural Science Foundation of China (Grant No. 10905080, 11075191 and 11205217).
QL designed and supervised the study. XZ, XJ and FL performed the experiments. XZ wrote the manuscript. XL and YL analyzed the data. FY, PL and TZ contributed to the data analysis and discussion. XZ and FL performed the irradiation. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care Committee and with the approval of the Academic Committee at Institute of Modern Physics.
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