title: Sub-chronic administration of LY294002 sensitizes cervical cancer cells to chemotherapy by enhancing mitochondrial JNK signaling.
abstract: Chemo-sensitization is used to improve the efficacy of chemotherapeutic agents against cancers, and understanding the precise molecular mechanisms of chemo-sensitization could lead to safer and more effective approaches to treat cancer. We have previously demonstrated that mitochondrial c-Jun N-terminal Kinase (JNK) signaling is a critical component of cell death. Mitochondrial JNK signaling is coordinated on the scaffold protein Sab. In this work, we developed a sub-chronic chemo-sensitization model by exposing HeLa cells to low-dose (2 μM) LY294002. We found that this treatment increased Sab expression on mitochondria, an effect not observed in acute exposures. To examine the role of Sab in chemo-sensitization, we ectopically expressed and silenced Sab in HeLa cells. We found that elevating Sab levels in HeLa cells increased the efficacy of chemotherapeutic agents, paclitaxel and cisplatin, while silencing Sab decreased the sensitivity of cells towards these agents. The effect of Sab-mediated signaling appeared to be dependent upon mitogen dependent protein kinases (MAPKs) as ablation of Sab's MAPK-binding motifs prevented chemo-sensitization. These results suggest that mitochondrial JNK signaling is an adaptable signaling pathway that can be enhanced or restored in cancer cells to improve therapeutic efficacy.
authors.affiliation: Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, USA.
authors.forename: Tara P
authors.initials: TP
authors.lastname: Chambers
authors.affiliation: Department of Biological Sciences, College of Arts and Sciences, USA.
authors.forename: Gilda M
authors.initials: GM
authors.lastname: Portalatin
authors.affiliation: Department of Cellular Biology and Pharmacology, USA.
authors.forename: Iru
authors.initials: I
authors.lastname: Paudel
authors.affiliation: Medical Academy for Science & Technology (MAST) Academy at Homestead, Homestead, FL, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Robbins
authors.affiliation: Department of Cellular Biology and Pharmacology, USA; Biomolecular Sciences Institute, Florida International University, USA. Electronic address: jwchambe@fiu.edu.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Chambers
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002867:Chromones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009025:Morpholines / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D015398:Signal Transduction / Q000187:drug effects*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048670:MAP Kinase Kinase 4
keywords: Chemo-sensitization; JNK; LY294002; Mitochondria; PI3K; Sab