The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer.

Abstract

BACKGROUND:

PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment.

METHODS:

The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP.

RESULTS:

By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently.

CONCLUSIONS:

The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

• Authors: Lei Zhang, Yidong Li, Qianchao Wang, Zhuo Chen, Xiaoyun Li, Zhuoxun Wu, Chaohua Hu, Dan Liao, Wei Zhang, Zhe-Sheng Chen
• Journal: Molecular cancer (Mol Cancer) Vol. 19 Issue 1 Pg. 10 (01 17 2020) ISSN: 1476-4598 [Electronic] England
• PMID: 31952518 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Biomarkers, Tumor
• Neoplasm Proteins
• Protein Kinase Inhibitors
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• PIK3CB protein, human

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (genetics, metabolism)
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Squamous Cell (drug therapy, genetics, metabolism, pathology)
• Cell Proliferation
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Proteins (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Tumor Cells, Cultured