title: B7-H4 downregulation induces mitochondrial dysfunction and enhances doxorubicin sensitivity via the cAMP/CREB/PGC1-α signaling pathway in HeLa cells.
abstract: B7-H4 is a B7 family coregulatory protein that inhibits T cell-mediated immunity. B7-H4 is overexpressed in various cancers; however, the functional role of B7-H4 in cancer metabolism is poorly understood. Because mitochondria play pivotal roles in development, proliferation, and death of cancer cells, we investigated molecular and functional alterations of mitochondria in B7-H4-depleted HeLa cells. In a human study, overexpression of B7-H4 was confirmed in the cervices of adenocarcinoma patients (n = 3) compared to noncancer patients (n = 3). In the cell line model, B7-H4 depletion was performed by transfection with small interfering RNA (siRNA). B7-H4 depletion suppressed oxygen consumption rate, ATP production, and mitochondrial membrane potential and mass and increased reactive oxygen species production. In particular, electron transport complex III activity was significantly impaired in siB7-H4-treated cells. Coincidently, depletion of B7-H4 suppressed major mitochondrial regulators (peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC1-α] and mitochondrial transcription factor A), a component of oxidative phosphorylation (ubiquinol-cytochrome c reductase core protein 1), and an antiapoptosis protein (Bcl-XL). Mitochondrial dysfunction in siRNA-treated cells significantly augmented oxidative stress, which strongly activated the JNK/P38/caspase axis in the presence of doxorubicin, resulting in increased apoptotic cell death. Investigating the mechanism of B7-H4-mediated mitochondrial modulation, we found that B7-H4 depletion significantly downregulated the cAMP/cAMP response element-binding protein/PGC1-α signaling pathway. Based on these findings, we conclude that B7-H4 has a role in the regulation of mitochondrial function, which is closely related to cancer cell physiology and drug sensitivity.
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: In-Sung
authors.initials: IS
authors.lastname: Song
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Jeong
authors.forename: Sung Ryul
authors.initials: SR
authors.lastname: Lee
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Heo
authors.forename: Vu Thi
authors.initials: VT
authors.lastname: Thu
authors.forename: Nari
authors.initials: N
authors.lastname: Kim
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Ko
authors.forename: Byoung Doo
authors.initials: BD
authors.lastname: Rhee
authors.forename: Dae Hun
authors.initials: DH
authors.lastname: Jeong
authors.forename: Young Nam
authors.initials: YN
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Han
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D017362:Cyclic AMP Response Element-Binding Protein; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D004317:Doxorubicin; D000242:Cyclic AMP