Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells. Academic Article uri icon

Overview

abstract

  • Serine/one-carbon metabolism provides critical resources for nucleotide biosynthesis and epigenetic maintenance and is thus necessary in cancer cell growth, although the detailed regulatory mechanisms remain unclear. We uncover a critical role of glycogen synthase kinase 3 (GSK3) in regulating the expression of serine/one-carbon metabolic enzymes. Nuclear enrichment of GSK3 significantly suppresses genes that mediate de novo serine synthesis, including PHGDH, PSAT1, PSPH, and one-carbon metabolism, including SHMT2 and MTHFD2. FRAT1 promotes nuclear exclusion of GSK3, enhances serine/one-carbon metabolism, and, as a result, confers cell vulnerability to inhibitors that target this metabolic process such as SHIN1, a specific SHMT1/2 inhibitor. Furthermore, pharmacological or genetic suppression of GSK3 promotes serine/one-carbon metabolism and exhibits a significant synergistic effect in combination with SHIN1 in suppressing cancer cell proliferation in cultured cells and in vivo. Our observations indicate that inhibition of nuclear GSK3 signaling creates a vulnerability, which results in enhanced efficacy of serine/one-carbon metabolism inhibitors for the treatment of cancer.

publication date

  • May 20, 2022

Research

keywords

  • Lung Neoplasms
  • Serine

Identity

PubMed Central ID

  • PMC9122323

Scopus Document Identifier

  • 85130586340

Digital Object Identifier (DOI)

  • 10.1126/sciadv.abm8786

PubMed ID

  • 35594343

Additional Document Info

volume

  • 8

issue

  • 20