Journal
MOLECULAR CANCER RESEARCH
Volume 12, Issue 1, Pages 48-57Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-13-0258-T
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Funding
- LAM Foundation
- Adler Foundation
- Tuberous Sclerosis Alliance
- National Institute of Diabetes and Digestive and Kidney Diseases
- NIH [5P01CA120964-04]
- NIH DF/HCC
- Cancer Center [P30CA006516-46]
- National Heart, Lung, and Blood Institute
- National Cancer Institute
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The mammalian target of rapamycin complex 1 (mTORC1) is hyperactive in many human cancers and in tuberous sclerosis complex (TSC). Autophagy, a key mTORC1-targeted process, is a critical determinant of metabolic homeostasis. Metabolomic profiling was performed to elucidate the cellular consequences of autophagy dysregulation under conditions of hyperactive mTORC1. It was discovered that TSC2-null cells have distinctive autophagy-dependent pentose phosphate pathway (PPP) alterations. This was accompanied by enhanced glucose uptake and utilization, decreased mitochondrial oxygen consumption, and increased mitochondrial reactive oxygen species (ROS) production. Importantly, these findings revealed that the PPP is a key autophagy-dependent compensatory metabolic mechanism. Furthermore, PPP inhibition with 6-aminonicotinamide (6-AN) in combination with autophagy inhibition suppressed proliferation and prompted the activation of NF-kappa B and CASP1 in TSC2-deficient, but not TSC2-proficient cells. These data demonstrate that TSC2-deficient cells can be therapeutically targeted, without mTORC1 inhibitors, by focusing on their metabolic vulnerabilities.
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