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Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress

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Abstract

Autophagy plays a crucial role in cancer cell survival and the inhibition of autophagy is attracting attention as an emerging strategy for the treatment of cancer. Chloroquine (CQ) is an anti-malarial drug, and is also known as an inhibitor of autophagy. Recently, it has been found that CQ induces cancer cell death through the inhibition of autophagy; however, the underlying mechanism is not entirely understood. In this study, we identified the role of CQ-induced cancer cell death using Primary Effusion Lymphoma (PEL) cells. We found that a CQ treatment induced caspase-dependent apoptosis in vitro. CQ also suppressed PEL cell growth in a PEL xenograft mouse model. We showed that CQ activated endoplasmic reticulum (ER) stress signal pathways and induced CHOP, which is an inducer of apoptosis. CQ-induced cell death was significantly decreased by salbrinal, an ER stress inhibitor, indicating that CQ-induced apoptosis in PEL cells depended on ER stress. We show here for the first time that the inhibition of autophagy induces ER stress-mediated apoptosis in PEL cells. Thus, the inhibition of autophagy is a novel strategy for cancer chemotherapy.

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Acknowledgments

We thank Ms. I. Suzu and Ms. S. Fujikawa for their technical assistance and Ms. Y. Kanagawa for her secretarial assistance. This work was supported by the Research program on HIV/AIDS (No. 16fk0410108h0001) from the Japan Agency for Medical Research and Development, AMED, and Grants-in-Aid for Science Research (No. 16K08742) from the Ministry of Education, Science, Sports, and Culture of Japan.

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Authors and Affiliations

  1. Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1, Honjo, Kumamoto, 860-0811, Japan

    Md. Masud Alam, Ryusho Kariya, Azusa Kawaguchi, Kouki Matsuda, Eriko Kudo & Seiji Okada

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  1. Md. Masud Alam
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  2. Ryusho Kariya
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  3. Azusa Kawaguchi
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  4. Kouki Matsuda
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  6. Seiji Okada
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Correspondence to Seiji Okada.

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Masud Alam, M., Kariya, R., Kawaguchi, A. et al. Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress. Apoptosis 21, 1191–1201 (2016). https://doi.org/10.1007/s10495-016-1277-7

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