Combining GRP78 suppression and MK2206-induced Akt inhibition decreases doxorubicin-induced P-glycoprotein expression and mitigates chemoresistance in human osteosarcoma.

Abstract

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.

• Authors: Yuan-Zheng Xia, Lei Yang, Gui-Min Xue, Chao Zhang, Chao Guo, Yan-Wei Yang, Shan-Shan Li, Lu-Yong Zhang, Qing-Long Guo, Ling-Yi Kong
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 35 Pg. 56371-56382 (Aug 30 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27486760 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• Heterocyclic Compounds, 3-Ring
• Hspa5 protein, mouse
• MK 2206
• RNA, Small Interfering
• Doxorubicin
• Proto-Oncogene Proteins c-akt

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (drug effects)
• Endoplasmic Reticulum Chaperone BiP
• Female
• Heat-Shock Proteins (genetics, metabolism)
• Heterocyclic Compounds, 3-Ring (pharmacology, therapeutic use)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Osteosarcoma (drug therapy, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Up-Regulation
• Xenograft Model Antitumor Assays