TY - JOUR
T1 - PEG-GO@XN nanocomposite suppresses breast cancer metastasis via inhibition of mitochondrial oxidative phosphorylation and blockade of epithelial-to-mesenchymal transition
AU - Zhang, Jialing
AU - Yan, Liang
AU - Wei, Peng
AU - Zhou, Ruyi
AU - Hua, Chaoju
AU - Xiao, Min
AU - Tu, Yaping
AU - Gu, Zhanjun
AU - Wei, Taotao
N1 - Funding Information:
Jialing Zhang, Liang Yan and Peng Wei contributed equally to this work. The authors thank Prof. Hiromi Imamura (Kyoto University, Japan) for providing ATP biosensor AT1.03. The authors are also indebted to Drs. Ying Liu, Jing Liu, and Jinglong Tang (NCNST, China) for technical assistances. This work was supported by grants from the National Key R&D Program of China ( 2017YFA0205501 ) and the National Natural Science Foundation of China ( 92054108 , 31771257 and 31671175 ).
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/3/15
Y1 - 2021/3/15
N2 - Metastatic breast cancer is a significant contributor to mortality among women, but its complex regulation represents a barrier to precision targeting. In the present study, a graphene-based nanocomposite which probes and selectively inhibits cancer cell motility is described. By controllable coupling of prenylated chalcone xanthohumol, an efficient inhibitor of mitochondrial electron transport chain complex I, with PEGylated graphene oxide nanosheet, a PEG-GO@XN nanocomposite with good stability and biocompatibility is synthesized. PEG-GO@XN is capable of inhibiting mitochondrial oxidative phosphorylation selectively in MDA-MB-231 and MDA-MB-436 metastatic breast cancer cells. PEG-GO@XN reduces the production of ATP, impairs the formation of F-actin cytoskeleton in the lamellipodia, and blocks the migration and invasion of breast cancer cells in vitro, without interfering the proliferation and metabolism of non-cancerous cells. More importantly, PEG-GO@XN suppresses the metastasis of MDA-MB-231 cells to lung in nude mice. PEG-GO@XN abolishes the TGF-β1-induced down-regulation of E-cadherin and up-regulation of N-cadherin, vimentin, Snail and Twist, thus causes the maintenance of “epithelial-like” rather than the “mesenchymal-like” features, and decreases the motility potential of breast cancer cells. Taken together, this research unveils the enormous potential of PEG-GO@XN to suppress metastatic breast cancer by selective targeting oxidative phosphorylation and epithelial-mesenchymal transition of cancer cells and thereby providing insights on metastatic cancer treatment.
AB - Metastatic breast cancer is a significant contributor to mortality among women, but its complex regulation represents a barrier to precision targeting. In the present study, a graphene-based nanocomposite which probes and selectively inhibits cancer cell motility is described. By controllable coupling of prenylated chalcone xanthohumol, an efficient inhibitor of mitochondrial electron transport chain complex I, with PEGylated graphene oxide nanosheet, a PEG-GO@XN nanocomposite with good stability and biocompatibility is synthesized. PEG-GO@XN is capable of inhibiting mitochondrial oxidative phosphorylation selectively in MDA-MB-231 and MDA-MB-436 metastatic breast cancer cells. PEG-GO@XN reduces the production of ATP, impairs the formation of F-actin cytoskeleton in the lamellipodia, and blocks the migration and invasion of breast cancer cells in vitro, without interfering the proliferation and metabolism of non-cancerous cells. More importantly, PEG-GO@XN suppresses the metastasis of MDA-MB-231 cells to lung in nude mice. PEG-GO@XN abolishes the TGF-β1-induced down-regulation of E-cadherin and up-regulation of N-cadherin, vimentin, Snail and Twist, thus causes the maintenance of “epithelial-like” rather than the “mesenchymal-like” features, and decreases the motility potential of breast cancer cells. Taken together, this research unveils the enormous potential of PEG-GO@XN to suppress metastatic breast cancer by selective targeting oxidative phosphorylation and epithelial-mesenchymal transition of cancer cells and thereby providing insights on metastatic cancer treatment.
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U2 - 10.1016/j.ejphar.2021.173866
DO - 10.1016/j.ejphar.2021.173866
M3 - Article
C2 - 33454376
AN - SCOPUS:85099627730
VL - 895
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
M1 - 173866
ER -