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Author Notes:

Lead Contact: Sumin Kang, 1365C Clifton Rd NE, C3006, Emory University School of Medicine, Atlanta, GA 30322; Tel.: 404-778-1880; Fax: 404-778-5520; smkang@emory.edu

Y.K., F.R.K., C.-K.Q., and T.K.O. provided critical resources.

Z.L. performed structural analyses.

K.R.M. performed histopathological study.

W.-M.Y. investigated the Seahorse XF assays.

A.K. and C.M. performed isotope tracing.

G.Z. investigated patient-derived xenograft.

L.J., J.C., C.P., Y.H. D.L., and G.N.A. performed all other experiments.

L.J. did project administration and data analysis of the study.

S.K. supervised the study and wrote the paper.

We acknowledge Dr. Anthea Hammond for editorial assistance.

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Research Funding:

This work was supported in part by NIH grants R01 CA175316 (S.K.), R01 CA207768 (S.K.), R01 CA188652 (C.M.), DoD W81XWH-17-1-0186 (S.K.), and Developmental Funds from the Winship Cancer Institute of Emory University (S.K.).

F.R.K., and S.K. are Georgia Cancer Coalition Scholars.

S. K is a Robbins Scholar and an American Cancer Society Basic Research Scholar.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • EXTRACELLULAR-MATRIX
  • REDOX HOMEOSTASIS
  • AMPK
  • METABOLISM
  • INHIBITION
  • GROWTH
  • CELLS
  • PHOSPHORYLATION
  • ANTIOXIDANT
  • SUPPRESSOR

The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer

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Journal Title:

Molecular Cell

Volume:

Volume 69, Number 1

Publisher:

, Pages 87-+

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer. Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis promotes tumor metastasis remains unclear. In this article, Jin et al. demonstrate a mechanism by which GDH1 provides anti-anoikis and pro-metastatic signals through activating CamKK2 and AMPK that promotes tumor metastasis in LKB1-deficient lung cancer.

Copyright information:

© 2017 Elsevier Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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