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

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.

HIF‐1α mediates CXCR4 transcription to activate the AKT/mTOR signaling pathway and augment the viability and migration of activated B cell‐like diffuse large B‐cell lymphoma cells

“…Activation of the Akt/mTOR has been reportedly linked to the oncogenic events mediated by CXCR4 14,15 . The expression of CXCR4 and AKT/mTOR pathway‐related proteins were detected by western blot assay.…”

Autophagy and its role in osteosarcoma

“…97 More importantly, a recent study of Liao et al pointed out that CXCR4 blocker increased DOX sensitivity of OS through activating autophagic cell death by negatively regulating PI3K/ AKT/mTOR signaling pathway. 98 We conclude from above that mild autophagy could increase chemoresistance because of cytoprotective effect, whereas excessive autophagy reverses chemoresistance through activating cell death (Table 1). Thus, our study has important guiding significance in developing autophagy inhibitors or autophagy activators to modulate chemoresistance of OS in the future.…”

“…Similarly, as an autophagy inducer, voacamine could enhance the chemosensitivity of DOX‐resistant U2OS cells through activating autophagic cell death 97 . More importantly, a recent study of Liao et al pointed out that CXCR4 blocker increased DOX sensitivity of OS through activating autophagic cell death by negatively regulating PI3K/AKT/mTOR signaling pathway 98 …”

“… 97 More importantly, a recent study of Liao et al pointed out that CXCR4 blocker increased DOX sensitivity of OS through activating autophagic cell death by negatively regulating PI3K/AKT/mTOR signaling pathway. 98 …”

CXCL12 secreted by pancreatic stellate cells accelerates gemcitabine resistance of pancreatic cancer by enhancing glycolytic reprogramming

“…PI3K/AKT/mTOR signaling also participates in GEM resistance of PC cells by regulating the Warburg effect (Cui et al 2021 ). Moreover, PI3K/AKT/mTOR signaling is reported to be the downstream signaling pathway after the activation of CXCR4 (Yi et al 2019 ; Yi and Gao 2019 ; Liao et al 2021 ). In this study, we found that CXCL12 secreted by PSCs could bind to CXCR4 and then activate PI3K/AKT/mTOR signaling in PC cells.…”