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MTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability.

ABSTRACT: Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.

SUBMITTER: Gremke N

PROVIDER: S-EPMC7499183 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability.

Gremke Niklas N Polo Pierfrancesco P Dort Aaron A Schneikert Jean J Elmshäuser Sabrina S Brehm Corinna C Klingmüller Ursula U Schmitt Anna A Reinhardt Hans Christian HC Timofeev Oleg O Wanzel Michael M Stiewe Thorsten T

Nature communications 20200917 1

Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerabilit ...[more]

PMID: 32943635

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Project description:BackgroundOsteosarcoma is the most common primary bone tumor in children and adolescents. Unfortunately, osteosarcoma treatments often fail due to the development of chemoresistance, of which the underlying molecular mechanisms still remain unclear. In this study, we demonstrated that HSP90AA1 gene is responsible for drug resistance in osteosarcoma through an autophagy-related mechanism.MethodsshRNAs were transfected into osteosarcoma cells for knockdown of HSP90AA1 gene. Stable HSP90AA1 overexpressing osteosarcoma cell lines were obtained by lentivirus infection. mRNA and protein expressions of HSP90AA1 in osteosarcoma cells were tested by quantitative real-time PCR and western blot, respectively. Autophagy of osteosarcoma cells was detected by western blot of LC3, transmission electron microscopy and fluorescence microscope. mRFP-GFP-LC3 lentiviral transfection was also performed to detect autophagic flux. NOD/SCID mices were inoculated with MG-63 tumor cells transfected with HSP90AA1 specific shRNA. TUNEL and LC3 staining were performed to detect apoptosis and autophagy of resected tumor tissues.ResultsDoxorubicin, cisplatin, and methotrexate, which are commonly used in chemotherapy, each induced HSP90AA1 upregulation in human osteosarcoma cells. Suppression of HSP90AA1 restored the sensitivity of osteosarcoma cells to chemotherapy both in vivo and in vitro. Mechanism study indicated that autophagy is responsible for the chemoresistance in osteosarcoma cells. HSP90AA1 increased drug resistance by inducing autophagy and inhibiting apoptosis. Suppression of HSP90AA1 diminished autophagic protection in response to chemotherapy in osteosarcoma cells. Moreover, HSP90AA1 promotes autophagy through PI3K/Akt/mTOR pathway and inhibits apoptosis through JNK/P38 pathway.ConclusionWe showed that chemotherapy agents can induce HSP90AA1 expression in osteosarcoma cells. And HSP90AA1, acting as an important regulator of autophagy, is a critical factor in the development of osteosarcoma chemoresistance both in vitro and in vivo. HSP90AA1 provides a novel therapeutic target for improving osteosarcoma treatment.

Dataset Information

MTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability.

Publications

mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability.

Similar Datasets

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