| First Author | Kovalenko A | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 8 | Pages | 2086-2100 |
| PubMed ID | 33593821 | Mgi Jnum | J:305546 |
| Mgi Id | MGI:6706794 | Doi | 10.1158/0008-5472.CAN-20-2218 |
| Citation | Kovalenko A, et al. (2021) Therapeutic targeting of DGKA-mediated macropinocytosis leads to phospholipid reprogramming in Tuberous Sclerosis Complex. Cancer Res |
| abstractText | Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In LAM, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high throughput screen utilizing the "Repurposing" library at the Broad Institute, with or without the autophagy inhibitor chloroquine. Ritanserin, an inhibitor of diacylglycerol kinase alpha (DGKA), was identified as a selective inhibitor of proliferation of Tsc2-/- MEFs, with no impact on Tsc2+/+ MEFs. DGKA is a lipid kinase that metabolizes diacylglycerol (DAG) to phosphatidic acid (PA), a key component of plasma membranes. PA levels were increased 5-fold in Tsc2-/- MEFs compared to Tsc2+/+ MEFs, and treatment of Tsc2-/- MEFs with ritanserin led to depletion of PA as well as rewiring of phospholipid metabolism. Macropinocytosis is known to be upregulated in TSC2-deficient cells. Ritanserin decreased macropinocytic uptake of albumin, limited the number of lysosomes, and reduced lysosomal activity in Tsc2-/- MEFs. In a mouse model of TSC, ritanserin treatment decreased cyst frequency and volume, and in a mouse model of LAM, genetic downregulation of DGKA prevented alveolar destruction and airspace enlargement. Collectively, these data indicate that DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis and promote proliferation. Targeting macropinocytosis with ritanserin may represent a novel therapeutic approach for the treatment of TSC and LAM. |
