Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling
0
조회
0
다운로드
0
인용
0
참고문헌
초록
Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.
Abstract
Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.
참고문헌 (45)
- Sahort, N. J., "Acute myeloid leukaemia", Lancet, 392, pp.593~606 (2018)
- Siegel, R. L., "Cancer statistics, 2020", CA Cancer J. Clin, 70, pp.7~30 (2020)
- Miller, K. D., "Cancer treatment and survivorship statistics, 2019", CA Cancer J. Clin, 69, pp.363~385 (2019)
- Zuckerman, T., "How I treat hematologic emergencies in adults with acute leukemia", Blood, 120, pp.1993~2002 (2012)
- Socie, G., "Current issues in chronic graft-versus-host disease", Blood, 124, pp.374~384 (2014)
- Mcnerney, M. E., "Therapy-related myeloid neoplasms : when genetics and environment collide", Nat. Rev. Cancer, 17, pp.513~527 (2017)
- White, E., "Deconvoluting the context-dependent role for autophagy in cancer", Nat. Rev. Cancer, 12, pp.401~410 (2012)
- White, E., "The role for autophagy in cancer", J. Clin. Investig, 125, pp.42~46 (2015)
- Levy, J. M., "Targeting autophagy during cancer therapy to improve clinical outcomes", Pharmacol. Ther, 131, pp.130~141 (2011)
- Altman, J. K., "Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2", mTORC1 targeting, 2014, pp.20, 2400~2409
- Sehgal, A. R., "You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia", Leukemia, 29, pp.517~525 (2015)
- Auberger, P., "Autophagy, a key mechanism of oncogenesis and resistance in leukemia", Blood, 129, pp.547~552 (2017)
- Isakson, P., "Autophagy contributes to therapy-induced degradation of the PML", RARA oncoprotein, 2010, pp.116, 2324~2331
- Zhuo, W., "Autophagy regulates myeloid cell differentiation by p62", SQSTM1-mediated degradation of PML-RARalpha oncoprotein, 2011, pp.7, 401~411
- Goussetis, D. J., "Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide", Blood, 120, pp.3555~3562 (2012)
- Amaravadi, R. K., "Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma", J. Clin. Investig, 117, pp.326~336 (2007)
- Chittaranjan, S., "Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and-resistant triple-negative breast cancer", Clin. Cancer Res, 20, pp.3159~3173 (2014)
- Palmeira Dos Santos, C., "Comparative study of autophagy inhibition by 3MA and CQ on Cytarabineinduced death of leukaemia cells", J. Cancer Res. Clin. Oncol, 140, pp.909~920 (2014)
- Yaping, Y., "Application and interpretation of current autophagy inhibitors and activators", Acta Pharmacol. Sin, 34, pp.625~635 (2013)
- Kimura, T., "Chloroquine in cancer therapy : a double-edged sword of autophagy", Cancer Res, 73, pp.3~7 (2013)
- Levy, J. M. M., "Targeting autophagy in cancer", Nat. Rev. Cancer, 17, pp.528~542 (2017)
- Gordon D. Brown, "Lectin Receptors Expressed on Myeloid Cells", Microbiology Spectrum, 4(5) (2016), American Society for Microbiology[DOI]
- Agarwal, V., "Streptococcus pneumoniae endopeptidase O(PepO)is a multifunctional plasminogen-and fibronectin-binding protein, facilitating evasion of innate immunity and invasion of host cells", J. Biol. Chem, 288, pp.6849~6863 (2013)
- Yusi, L., "Mucosal immunization with recombinant fusion protein DnaJDeltaA146Ply enhances cross-protective immunity against Streptococcus pneumoniae infection in mice via interleukin 17A", Infect. Immun, 82, pp.1666~1675 (2014)
- Klusmann, J. H., "Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis", Genes Dev, 24, pp.1659~1672 (2010)
- Janes, M. R., "Effective and selective targeting of leukemia cells using a TORC1", 2 kinase inhibitor, 2010, pp.16, 205~213
- Kojima, K., "The dual PI3 kinase", mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53wild-type AML, 2008, pp.22, 1728~1736
- Stankov, M. V., "Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy", Leukemia, 28, pp.577~588 (2014)
- Gargalionis, A. N., "Polycystin-1 downregulation induces ERK-dependent mTOR pathway activation in a cellular model of psoriasis", Biochim. Biophys. Acta Mol. Basis Dis, 1864, pp.3468~3476 (2018)
- Pathak, P., "Genetic alterations related to BRAF-FGFR genes and dysregulated MAPK", ERK, Brain Pathol, pp.2017, 27[DOI]
- Lina, B., "Allicin attenuates pathological cardiac hypertrophy by inhibiting autophagy via activation of PI3K", Akt, ERK, pp.mTOR signaling pathways, Phytomedicine[DOI]
- Dandan, X., "Orexin-A protects against cerebral ischemia-reperfusion injury by inhibiting excessive autophagy through OX1R-mediated MAPK", ERK, Cell Signal, pp.2021, 79[DOI]
- Kondo, Y., "The role of autophagy in cancer development and response to therapy", Nat. Rev. Cancer, 5, pp.726~734 (2005)
- Gewirtz, D. A., "The four faces of autophagy: implications for cancer therapy", Cancer Res, 74, pp.647~651 (2014)
- Gewirtz, D. A., "When cytoprotective autophagy isn’t… and even when it is", Autophagy, 10, pp.391~392 (2014)
- Elmore, S., "Apoptosis : a review of programmed cell death", Toxicol. Pathol, 35, pp.495~516 (2007)
- Voss, A. K., "The essentials of developmental apoptosis", F1000Res, 26(9) (2020)
- Rebecca, V. W., "Emerging strategies to effectively target autophagy in cancer", Oncogene, 35, pp.1~11 (2016)
- Roy, S., "Microbiota : a key orchestrator of cancer therapy", Nat. Rev. Cancer, 17, pp.271~285 (2017)
- Zitvogel, L., "Anticancer effects of the microbiome and its products", Nat. Rev. Microbiol, 15, pp.465~478 (2017)
- Pham, J. V., "A review of the microbial production of bioactive natural products and biologics", Front. Microbiol, 10, pp.1404~ (2019)
- Nauts, H. C., "The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research", Cancer Res, 6, pp.205~216 (1946)
- Babjuk, M., "EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013", Eur. Urol, 64, pp.639~653 (2013)
- Malla, S., "Limitations in doxorubicin production from Streptomyces peucetius", Microbiol. Res, 165, pp.427~435 (2010)
- Hong, Z., "Combination of detoxified pneumolysin derivative deltaa146ply and berbamine as a treatment approach for breast cancer", Mol. Ther. Oncolytics, 18, pp.247~261 (2020)