CXCR4 blockade sensitizes osteosarcoma to doxorubicin by inducing autophagic cell death via PI3K‑Akt‑mTOR pathway inhibition

Liao,Yu-Xin; Lv,Ji-Yang; Zhou,Zi-Fei; Xu,Tian-Yang; Yang,Dong; Gao,Qiu-Ming; Fan,Lin; Li,Guo-Dong; Yu,Hai-Yang; Liu,Kai-Yuan

doi:10.3892/ijo.2021.5229

CXCR4 blockade sensitizes osteosarcoma to doxorubicin by inducing autophagic cell death via PI3K‑Akt‑mTOR pathway inhibition

Authors:
- Yu-Xin Liao
- Ji-Yang Lv
- Zi-Fei Zhou
- Tian-Yang Xu
- Dong Yang
- Qiu-Ming Gao
- Lin Fan
- Guo-Dong Li
- Hai-Yang Yu
- Kai-Yuan Liu
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Affiliations: Department of Orthopaedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China, State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
Published online on: May 31, 2021 https://doi.org/10.3892/ijo.2021.5229
Article Number: 49
Copyright: © Liao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Doxorubicin is one of the most frequently used chemotherapy drugs in the treatment of osteosarcoma (OS), but the emergence of chemoresistance often leads to treatment failure. C‑X‑C motif chemokine receptor 4 (CXCR4) has been demonstrated to regulate OS progression and metastasis. However, whether CXCR4 is also involved in OS chemoresistance and its molecular mechanisms has yet to be fully elucidated. In the present study, CXCR4‑mediated autophagy for OS chemotherapy was investigated by western blot analysis, transmission electron microscopy and confocal microscopy. CXCR4 silencing enhanced doxorubicin‑induced apoptosis by reducing P‑glycoprotein in CXCR4⁺ LM8 cells, while CXCR4 overexpression promoted OS doxorubicin resistance in CXCR4^‑ Dunn cells. Furthermore, CXCR4 silencing with or without doxorubicin increased the expression of beclin 1 and light chain 3B, and the number of autophagosomes and autolysosomes, as well as induced autophagic flux activation by suppressing the PI3K/AKT/mTOR signaling pathway. In addition, pretreatment with the autophagy inhibitor bafilomycin A1 attenuated CXCR4 abrogation‑induced cell death. Finally, the CXCR4 antagonist AMD3100 synergistically reinforced the antitumor effect of doxorubicin in an orthotopic OS mouse model. Taken together, the present study revealed that CXCR4 inhibition sensitizes OS to doxorubicin by inducing autophagic cell death. Therefore, targeting the CXCR4/autophagy axis may be a promising therapeutic strategy to overcome OS chemotherapy resistance.

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