Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain and spinal tumors are the second most common malignancies in childhood after leukemia, and they remain the leading cause of death from childhood cancer. Autophagy is a catabolic cellular process that is thought to regulate chemosensitivity, however its role in pediatric tumors is unknown. Here we present studies in pediatric medulloblastoma cell lines (DAOY, ONS76) and atypical teratoid/rhabdoid tumor cell lines (BT-16, BT-12) to test this role. Autophagy was inhibited using siRNA against autophagy-related genes ATG12 and ATG7 or pharmacologically induced or inhibited using rapamycin and chloroquine to test the effect of autophagy on chemosensitivity. Autophagic flux was measured using Western blot analysis of LC3-II and p62 and cell viability was determined using MTS assays and clonogenic growth. We found that when pediatric brain tumor cells under starvation stress, exposed to known autophagy inducers such as rapamycin, or treated with current chemotherapeutics (lomustine, cisplatin), all stimulate autophagy. Silencing ATG12 and ATG7 or exposure to a known autophagy inhibitor, chloroquine, could inhibit this autophagy increase; however, the effect of autophagy on tumor cell killing was small. These results may have clinical relevance in the future planning of therapeutic regimens for pediatric brain tumors.
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PMID:Modulation of pediatric brain tumor autophagy and chemosensitivity. 2184 12

Medulloblastoma is a highly malignant pediatric brain tumor. About 30% patients have metastasis at diagnosis and respond poorly to treatment. Those that survive, suffer long term neurocognitive, endocrine and developmental defects due to the cytotoxic treatment to developing child brain. It is therefore necessary to develop targeted treatment strategies based on underlying biology for effective treatment of medulloblastoma with minimal side effects. Medulloblastomas are believed to be the result of deregulated nervous system development as evident from the role of WNT and SHH developmental signaling pathways in pathogenesis of medulloblastomas. MicroRNAs are known to play vital roles in nervous system development as well as in cancer. MicroRNA profiling of medulloblastomas identified miR-30 family members' expression to be downregulated in medulloblastomas belonging to the four known molecular subgroups viz. WNT, SHH, Group 3 and Group 4 as compared to that in normal brain tissues. Furthermore, established medulloblastoma cell lines Daoy, D283 and D425 were also found to underexpress miR-30a. Restoration of miR-30a expression using inducible lentiviral vector inhibited proliferation, clonogenic potential and tumorigenicity of medulloblastoma cells. MiR-30a is known to target Beclin1, a mediator of autophagy. MiR-30a expression was found to downregulate Beclin1 expression and inhibit autophagy in the medulloblastoma cell lines as judged by downregulation of LC3B expression and its turnover upon chloroquine treatment and starvation induced autophagy induction. MiR-30a therefore could serve as a novel therapeutic agent for the effective treatment of medulloblastoma by inhibiting autophagy that is known to play important role in cancer cell growth, survival and malignant behavior.
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PMID:Restoration of miR-30a expression inhibits growth, tumorigenicity of medulloblastoma cells accompanied by autophagy inhibition. 2875 13