Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers. The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers.
Original language | American English |
---|---|
Pages (from-to) | 2317-2330.e8 |
Journal | Cell Reports |
Volume | 28 |
Issue number | 9 |
DOIs | |
State | Published - 27 Aug 2019 |
Externally published | Yes |
Bibliographical note
Funding Information:We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081, R01CA204302, R01CA211052, and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH/NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc. for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber. N.C. E.P. and T.G.B. conceived and designed the experiments and analyzed the data. N.C. E.P. M.K.M. P.G. D.V.A. G.H. V.O. J.J.Y. L.L. C.H.E. J.F. and E.C. performed the experiments. S.A. and W.W. analyzed microarray data. T.I. M.H. and W.A.W. analyzed TCGA tumor data. J.S. performed time-lapse microscopy and analyzed the data. B.A.B. helped N.C. with PTEN purification. E.V. J.R.J. B.W.N. J.V.D. and N.J.K. performed phospho-proteomics screen and analyzed the data. N.C. E.P. A.J.S. and T.G.B. wrote the manuscript with input from all authors. T.G.B. is an advisor to Array Biopharma, Revolution Medicines, Novartis, AstraZeneca, Takeda, Springworks, and Jazz Pharmaceuticals and receives research funding from Novartis and Revolution Medicines.
Funding Information:
We would like to thank all members of the Bivona laboratory for critical review of the manuscript and acknowledge funding support from NIH/NCI grants U54CA224081 , R01CA204302 , R01CA211052 , and R01CA169338 and the Pew Foundation and Stewart Foundation (to T.G.B.); U54 CA209891 (to N.J.K.); R01GM123159 (to J.S.F.); R01GM118939 (to Y.K.); and NIH / NCI T32CA108462-14 (to N.C.). We thank Timothy Fouts and Jeffrey Meshulam at Profectus Biosciences, Inc., for generously providing PBS-1086. We thank Bhagyashri Burgute and Angelika Noegel at the University of Cologne, Germany, for kindly providing the NKAP mouse mAb (K85-80-5). We thank Albertas Navickas and Hani Goodarzi at UCSF for the hypoxia chamber.
Publisher Copyright:
© 2019 The Author(s)
Keywords
- NF-κB
- NKAP
- PDHK1
- PTEN
- cancer
- metabolism
- protein phosphatase
- signaling
- synthetic lethality