title: Integrative molecular profiling reveals asparagine synthetase is a target in castration-resistant prostate cancer.
abstract: The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy-resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen-responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells.
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: ksircar@mdanderson.org.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.affiliation: Department of Computer Science and Engineering, The University of Texas Arlington, Arlington, Texas.
authors.forename: Heng
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Cogdell
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jasreman
authors.initials: J
authors.lastname: Dhillon
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Tzelepi
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Ismaël H
authors.initials: IH
authors.lastname: Koumakpayi
authors.affiliation: Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Department of Computer Science and Engineering, The University of Texas Arlington, Arlington, Texas.
authors.forename: Dijun
authors.initials: D
authors.lastname: Luo
authors.affiliation: Department of Pathology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Ana
authors.initials: A
authors.lastname: Aparicio
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Nora
authors.initials: N
authors.lastname: Navone
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Electronic address: wzhang@mdanderson.org.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001217:Aspartate-Ammonia Ligase / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004247:DNA; D001217:Aspartate-Ammonia Ligase