ABSTRACT
High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma. SIGNIFICANCE: Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma. See related commentary by Stouth et al., p. 2091.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Neuroblastoma , Mice , Animals , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Caffeine/pharmacology , Mevalonic Acid/metabolism , Simvastatin/pharmacology , Cholesterol , Mice, Transgenic , Neuroblastoma/drug therapy , Purinergic P1 Receptor Antagonists , Dietary Supplements , Forkhead Box Protein M1/geneticsABSTRACT
Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for high-grade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 µg/ml [0.4-1.7 µM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P<0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, ß-catenin, pß-Catenin(S552), Snail and Twist but increased levels of pß-Catenin(T41/S45), pGSK-3α/ß(S21/S9) and E-cadherin. sHA-F also inhibited CD44/Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL-1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P<0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment.
Subject(s)
Antineoplastic Agents/pharmacology , Hyaluronic Acid/pharmacology , Urinary Bladder Neoplasms/pathology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Hyaluronic Acid/chemistry , Mice , Phosphatidylinositol 3-Kinases/metabolism , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolism , Xenograft Model Antitumor AssaysABSTRACT
The study showed that under different degrees of Basilepta melanopus Lefevre stress, the kinds of aromatic constituents in the fresh leaves of Lingtou Dancong tea plant increased evidently, being the most (36 kinds) under medium stress. With the increase of the stress, the contents of 9 aromatic constituents like 1,6-methylene annulene increased, whereas those of 8 constituents as linalool decreased. Light stress induced the appearance of 4 aromatic constituents like 2-methyl hexadecane, while medium stress induced that of 6 constituents as H1-docosanol. Different degrees of B. melanopus stress could induce the synthesis of 23 aromatic constituents like 1,6-methylene annulene, but inhibit the formation of 6 constituents as nonanal.