A p110δ-specific inhibitor combined with bortezomib blocks drug resistance properties of EBV-related B cell origin cancer cells via regulation of NF-κB.
Epstein-Barr virus (EBV) infection is closely related to carcinogenesis of various cancers, and is also associated with the development of drug resistance in cancer stem cells. However, in EBV-positive cancer cells, the mechanistic details of the downstream signaling and the connection of PI3K with the NF-κB pathway for development of drug resistance remain controversial. Diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) cells infected by EBV display drug resistance-related proteins (MDR1, MRP1 and MRP2) and stem cell markers (OCT4 and SOX2). EBV-infected HT (HT/EBV) and H929 (H929/EBV) cells activated p110δ expression, but downregulated the expression of p110α and p110β. A combination of CAL-101, a p110δ-specific inhibitor, with bortezomib treatment of HT/EBV cells synergistically suppressed proliferation, reduced levels of drug resistance-related proteins, activated caspase cleavage and recovered expression of p110α/p110β. Additionally, co-treatment with CAL-101 and bortezomib attenuated the expression of OCT4 and SOX2 via inhibition of activated NF-κB. Co-treatment with CAL-101 and bortezomib also attenuated drug resistance and NF-κB activity of EBV-infected H929 cells. Our results provide supportive evidence for the clinical application of CAL-101 and bortezomib to treat EBV-infected hematologic cancer.
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
Ga Bin
GB
Park
Department of Anatomy, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea.
Yoon Hee
YH
Chung
Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea.
Jee-Yeong
JY
Jeong
Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.
Daejin
D
Kim
D000069286:Bortezomib / Q000008:administration & dosage; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D016328:NF-kappa B / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics*; D011687:Purines / Q000008:administration & dosage; D052999:Quinazolinones / Q000008:administration & dosage; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis
D016328:NF-kappa B; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011687:Purines; D052999:Quinazolinones; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000069286:Bortezomib; D019869:Phosphatidylinositol 3-Kinases; C552946:idelalisib