title: Rapamycin Suppresses Tumor Growth and Alters the Metabolic Phenotype in T-Cell Lymphoma.
abstract: The mTOR pathway is a master regulator of cellular growth and metabolism. The biosynthetic and energetic demand of rapidly proliferating cells such as cancer cells is met by metabolic adaptations such as an increased glycolytic rate known as the Warburg effect. Herein, we characterize the anti-tumor effect of rapamycin in a mouse model of T-cell lymphoma and examine the metabolic effects in vitro. The murine T-cell lymphoma line, MBL2, and human cutaneous T-cell lymphoma (CTCL) lines, HH and Hut78, were used in syngeneic or standard NSG mouse models to demonstrate a marked suppression of tumor growth by rapamycin accompanied by inhibition of mTORC1/2. Analysis of the metabolic phenotype showed a substantial reduction in the glycolytic rate and glucose utilization in rapamycin-treated lymphoma cells. This was associated with reduced expression of glucose transporters and glycolytic enzymes in cultured cells and xenograft tumors. As a result of the decrease in glycolytic state, rapamycin-treated cells displayed reduced sensitivity to low-glucose conditions but continued to rely on mitochondrial oxidative phosphorylation (OXPHOS) with sensitivity to inhibition of OXPHOS. Taken together, we demonstrate that rapamycin suppresses growth of T-cell lymphoma tumors and leads to a reduction in aerobic glycolysis counteracting the Warburg effect of cancer cells.
authors.affiliation: Departments of Dermatology, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Wasakorn
authors.initials: W
authors.lastname: Kittipongdaja
authors.affiliation: Departments of Dermatology, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Departments of Dermatology, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Garner
authors.affiliation: Departments of Dermatology, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Xiping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Komas
authors.affiliation: Departments of Dermatology, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Sam T
authors.initials: ST
authors.lastname: Hwang
authors.affiliation: Departments of Dermatology, Medical College of Wisconsin, Milwaukee, USA. Electronic address: sschieke@mcw.edu.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Schieke
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010641:Phenotype; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics*
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus