title: Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes.
abstract: BACKGROUND
  Cancer cells may undergo metabolic adaptations that support their growth as well as drug resistance properties. The purpose of this study is to test if oral cancer cells can overcome the metabolic defects introduced by using small interfering RNA (siRNA) to knock down their expression of important metabolic enzymes.
  
  
  METHODS
  UM1 and UM2 oral cancer cells were transfected with siRNA to transketolase (TKT) or siRNA to adenylate kinase (AK2), and Western blotting was used to confirm the knockdown. Cellular uptake of glucose and glutamine and production of lactate were compared between the cancer cells with either TKT or AK2 knockdown and those transfected with control siRNA. Statistical analysis was performed with student T-test.
  
  
  RESULTS
  Despite the defect in the pentose phosphate pathway caused by siRNA knockdown of TKT, the survived UM1 or UM2 cells utilized more glucose and glutamine and secreted a significantly higher amount of lactate than the cells transferred with control siRNA. We also demonstrated that siRNA knockdown of AK2 constrained the proliferation of UM1 and UM2 cells but similarly led to an increased uptake of glucose/glutamine and production of lactate by the UM1 or UM2 cells survived from siRNA silencing of AK2.
  
  
  CONCLUSIONS
  Our results indicate that the metabolic defects introduced by siRNA silencing of metabolic enzymes TKT or AK2 may be compensated by alternative feedback metabolic mechanisms, suggesting that cancer cells may overcome single defective pathways through secondary metabolic network adaptations. The highly robust nature of oral cancer cell metabolism implies that a systematic medical approach targeting multiple metabolic pathways may be needed to accomplish the continued improvement of cancer treatment.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Yang D
authors.initials: YD
authors.lastname: Chai
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Brumbaugh
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Liu
authors.forename: Ramin
authors.initials: R
authors.lastname: Rabii
authors.forename: Sizhe
authors.initials: S
authors.lastname: Feng
authors.forename: Kaori
authors.initials: K
authors.lastname: Misuno
authors.forename: Diana
authors.initials: D
authors.lastname: Messadi
authors.affiliation: UCLA School of Dentistry, 10083 Le Conte Ave, Los Angeles, CA 90095-1668, USA. shu@dentistry.ucla.edu.
authors.forename: Shen
authors.initials: S
authors.lastname: Hu
mesh_terms: D000263:Adenylate Kinase / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D064210:Secondary Metabolism; D014174:Transketolase / Q000037:antagonists & inhibitors*
chemical_list: D034741:RNA, Small Interfering; D005973:Glutamine; D019344:Lactic Acid; D014174:Transketolase; D000263:Adenylate Kinase; C110938:adenylate kinase 2; D005947:Glucose