title: GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner.
abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.forename: Lingjun
authors.initials: L
authors.lastname: Meng
authors.forename: Robert Y L
authors.initials: RY
authors.lastname: Tsai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009173:Mycophenolic Acid / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C469949:GNL3 protein, human; D009687:Nuclear Proteins; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins; D009173:Mycophenolic Acid; D017239:Paclitaxel; D005472:Fluorouracil