title: Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma.
abstract: Diffuse Large B cell lymphomas (DLBCL) are the most prevalent of the non-Hodgkin lymphomas and are currently initially treated fairly successfully, but frequently relapse as refractory disease, resulting in poor salvage therapy options and short survival. The greatest challenge in improving survival of DLBCL patients is overcoming chemo-resistance, whose basis is poorly understood. Among the potential mediators of DLBCL chemo-resistance is the thioredxoin (Trx) family, primarily because Trx family members play critical roles in the regulation of cellular redox homeostasis, and recent studies have indicated that dysregulated redox homeostasis also plays a key role in chemoresistance. In this study, we showed that most of the DLBCL-derived cell lines and primary DLBCL cells express higher basal levels of Trx-1 than normal B cells and that Trx-1 expression level is associated with decreased patients survival. Our functional studies showed that inhibition of Trx-1 by small interfering RNA or a Trx-1 inhibitor (PX-12) inhibited DLBCL cell growth, clonogenicity, and also sensitized DLBCL cells to doxorubicin-induced cell growth inhibition in vitro. These results indicate that Trx-1 plays a key role in cell growth and survival, as well as chemoresistance, and is a potential target to overcome drug resistance in relapsed/refractory DLBCL.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Changping
authors.initials: C
authors.lastname: Li
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Archito T
authors.initials: AT
authors.lastname: Tamayo
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Zuo
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ford
authors.forename: Lan V
authors.initials: LV
authors.lastname: Pham
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046228:Microarray Analysis; D058990:Molecular Targeted Therapy / Q000379:methods; D034741:RNA, Small Interfering / Q000494:pharmacology; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D013879:Thioredoxins