Related Experiment Video
Updated: May 5, 2026
Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide
Andrey A Parkhitko1, Carmen Priolo, Jonathan L Coloff
1Brigham and Women's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA 02115. cpriolo@partners.org.
Unlabelled:
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-κB 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.
Implications:
This study provides proof-of-concept that therapeutic targeting of diseases with hyperactive mTORC1 can be achieved without the application of mTORC1 inhibitors.
Insights
Targeting metabolic vulnerabilities in cancer cells with hyperactive mTORC1 is possible without mTORC1 inhibitors. This study reveals the pentose phosphate pathway (PPP) as a key autophagy-dependent mechanism in TSC2-deficient cells.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is common in human cancers and tuberous sclerosis complex (TSC).
- Autophagy is a critical process regulated by mTORC1, influencing metabolic homeostasis.
Purpose of the Study:
- To investigate the metabolic consequences of autophagy dysregulation in the context of hyperactive mTORC1.
- To identify potential therapeutic targets in TSC2-deficient cells.
Main Methods:
- Metabolomic profiling to analyze cellular changes.
- Assessment of glucose uptake, mitochondrial respiration, and reactive oxygen species (ROS) production.
- Inhibition of the pentose phosphate pathway (PPP) and autophagy.
Main Results:
- TSC2-null cells exhibit unique autophagy-dependent alterations in the PPP.
- These cells show increased glucose consumption, reduced mitochondrial oxygen use, and elevated mitochondrial ROS.
- The PPP acts as a crucial autophagy-dependent metabolic compensatory pathway.
- Combined PPP and autophagy inhibition suppressed proliferation and activated NF-κB and CASP1 in TSC2-deficient cells.
Conclusions:
- The pentose phosphate pathway is a key metabolic vulnerability in TSC2-deficient cells.
- Therapeutic strategies targeting metabolic pathways can be effective against diseases with hyperactive mTORC1, independent of mTORC1 inhibitors.
More Related Videos
19:44Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
Published on: May 30, 2012
07:49Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:27Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase