Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tuberous sclerosis complex 1 (TSC1) inhibits mammalian target of rapamycin (mTOR), a central promotor of cell growth and proliferation. The protein product of the TSC1 gene, hamartin (referred to as TSC1) is known to interact with Polo-like kinase 1 (Plk1) in a cell cycle regulated, phosphorylation-dependent manner. We hypothesized that the p53 target gene, Plk2, is a tumor suppressor, mediating its tumor suppressor function through interactions with TSC1 that facilitate TSC1/2 restraint of mTOR under hypoxic stress. We found that human lung tumor cells deficient in Plk2 grew larger than control tumors, and that Plk2 interacts with endogenous TSC1 protein. Additionally, C-terminal Plk2-GST fusion protein bound both TSC1 and TSC2 proteins. TSC1 levels were elevated in response to Adriamycin and cells transiently overexpressing Plk2 demonstrated decreased phosphorylation of the downstream target of mTOR, ribosomal protein p70S6 kinase during hypoxia. Plk2 levels were inversely correlated with cytoplasmic p70S6K phosphorylation. Plk2 levels did not increase in response to DNA damage (Adriamycin, CPT -11) when HCT 116 and H460 cells were exposed to hypoxia. TSC1-deficient mouse embryonic fibroblasts with TSC1 added back demonstrated decreased S6K phosphorylation, which was further decreased when Plk2 was transiently overexpressed. Interestingly, under normoxia, Plk2 deficient tumor cells demonstrated increased apoptosis in response to various chemotherapeutic agents including CPT -11 but increased resistance to apoptotic death after CPT-11 treatment under hypoxia, and tumor xenografts comprised of these Plk2-deficient cells were resistant to CPT -11. Our results point to a novel Plk2-TSC1 interaction with effects on mTOR signaling during hypoxia, and tumor growth that may enable targeting Plk2 signaling in cancer therapy.
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PMID:The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. 2005 36

A 40-year-old woman presented to a local clinic with abdominal distension. She was referred to our hospital for suspected ovarian cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovarian tumor with mural nodules, ascites, pleural effusion, and peritoneal dissemination. Laparotomy revealed a 20-cm right ovarian tumor with strong adhesion to the uterus and rectum. Bilateral salpingo-oophorectomy was performed as a primary surgery. The histopathological diagnosis was stage IVovarian clear cell adenocarcinoma, and 6 cycles of postoperative chemotherapy with a combination of TC (paclitaxel [PTX] and carboplatin) and the mTOR inhibitor temsirolimus was administered. During maintenance treatment with temsirolimus, the lesion recurred, and progressive disease was confirmed. Because relapse occurred after 5 months from the last TC treatment, the disease was considered platinum-resistant ovarian cancer, and second-line chemotherapy with 6 cycles of irinotecan (CPT-11 ) and PTX was administered. Partial response was observed after 2 cycles, and the response period was 7 months. We suggest that chemotherapy with CPT-11/PTX could be a treatment option for platinum resistant recurrent ovarian clear cell adenocarcinoma.
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PMID:[A case of platinum-resistant, recurrent ovarian clear cell adenocarcinoma successfully treated with irinotecan (CPT-11) and paclitaxel (PTX) chemotherapy]. 2543 51