TY - JOUR
T1 - KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition
AU - Koppula, Pranavi
AU - Olszewski, Kellen
AU - Zhang, Yilei
AU - Kondiparthi, Lavanya
AU - Liu, Xiaoguang
AU - Lei, Guang
AU - Das, Molina
AU - Fang, Bingliang
AU - Poyurovsky, Masha V.
AU - Gan, Boyi
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/6/25
Y1 - 2021/6/25
N2 - Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability.
AB - Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability.
KW - cancer
KW - cell biology
KW - physiology
UR - http://www.scopus.com/inward/record.url?scp=85107425429&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107425429&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.102649
DO - 10.1016/j.isci.2021.102649
M3 - Article
C2 - 34151236
AN - SCOPUS:85107425429
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 6
M1 - 102649
ER -