Combining GRP78 suppression and MK2206-induced Akt inhibition decreases doxorubicin-induced P-glycoprotein expression and mitigates chemoresistance in human osteosarcoma
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Yuan-Zheng Xia1, Lei Yang1, Gui-Min Xue1, Chao Zhang1, Chao Guo1, Yan-Wei Yang1, Shan-Shan Li1, Lu-Yong Zhang1, Qing-Long Guo1, Ling-Yi Kong1
1State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, People’s Republic of China
Ling-Yi Kong, email: firstname.lastname@example.org
Keywords: P-gp, GRP78, Akt, multidrug resistance, osteosarcoma
Received: January 17, 2016 Accepted: July 18, 2016 Published: July 28, 2016
P-glycoprotein (P-gp) overexpression is associated with poor prognosis and drug-resistance in osteosarcoma (OS), but the underlying mechanisms remain incompletely understood. Here, we examined the regulation of P-gp, GRP78, and phospho-Akt in doxorubicin (DOX)-treated OS cells. DOX induced P-gp expression, which was associated with increased GRP78 levels and Akt activation in vitro and in vivo. Functional analysis showed that Akt induces P-gp and GRP78 expression, which contributes to the DOX-induced Akt activation. Examination of the relationship between Akt and GRP78 demonstrated that GRP78 suppression attenuates the Akt activity in OS parental sensitive and resistant cells, indicating that GRP78 is required for full Akt activity. Inhibition of Akt activity using MK2206 decreased GRP78 expression in OS cells, which enhanced the inhibitory effect of MK2206 on P-gp expression. GRP78 knockdown combined with MK2206 suppressed the development of DOX resistance in OS cells and inhibited the in vivo tumor growth in the presence of DOX. These results support the development of novel therapeutic strategies that target GRP78 and Akt to sensitize OS cells for chemotherapy.
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