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

Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research.
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PMID:Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress. 2852 Dec 98