Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells

Significance The tumor suppressor syndrome tuberous sclerosis complex (TSC) affects 1:10,000 live births. We discovered that the inflammatory cytokine Interleukin-6 (IL-6) promotes the proliferation and migration of TSC2-deficient cells in part through the regulation of PSAT1 and de novo serine biosynthesis. Importantly, IL-6 neutralizing antibody treatments reduced renal cyst and cystadenoma formation in Tsc2+/− mice. This study highlights a therapeutically targetable vulnerability of TSC, which may have broad clinical application to mTORC1-activated tumors. Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2. Cytokine profiling of TSC2-deficient LAM patient–derived cells revealed striking up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wild-type cells. Treatment with anti–IL-6 (αIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2+/− mice while reducing PSAT1 expression. These data reveal a mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity.