Journal
CANCERS
Volume 11, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/cancers11050603
Keywords
DIRAS3; ARHI; autophagy; ovarian cancer; amino acid deprivation; tumor dormancy; mTOR; nutrient sensing
Categories
Funding
- MD Anderson SPOREs in Ovarian Cancer [NCI P50 CA 83639, NCI P50 CA217685]
- National Cancer Institute [R01 CA135354]
- Cancer Prevention and Research Institute of Texas [RP110595-P1]
- Shared Resources of the MD Anderson CCSG grant [NCI P30 CA16672]
- National Foundation for Cancer Research
- Ann and Sol Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund Alliance
- TRIUMPH Postdoctoral Fellowship program (CPRIT grant) [RP170067]
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Failure to cure ovarian cancer relates to the persistence of dormant, drug-resistant cancer cells following surgery and chemotherapy. Second look surgery can detect small, poorly vascularized nodules of persistent ovarian cancer in similar to 50% of patients, where >80% are undergoing autophagy and express DIRAS3. Autophagy is one mechanism by which dormant cancer cells survive in nutrient poor environments. DIRAS3 is a tumor suppressor gene downregulated in >60% of primary ovarian cancers by genetic, epigenetic, transcriptional and post-transcriptional mechanisms, that upon re-expression can induce autophagy and dormancy in a xenograft model of ovarian cancer. We examined the expression of DIRAS3 and autophagy in ovarian cancer cells following nutrient deprivation and the mechanism by which they are upregulated. We have found that DIRAS3 mediates autophagy induced by amino acid starvation, where nutrient sensing by mTOR plays a central role. Withdrawal of amino acids downregulates mTOR, decreases binding of E2F1/4 to the DIRAS3 promoter, upregulates DIRAS3 and induces autophagy. By contrast, acute amino acid deprivation did not affect epigenetic regulation of DIRAS3 or expression of miRNAs that regulate DIRAS3. Under nutrient poor conditions DIRAS3 can be transcriptionally upregulated, inducing autophagy that could sustain dormant ovarian cancer cells.
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