Abstract

Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells. Updegraff et al. show that transmembrane protease TMPRSS11B is upregulated in lung squamous cell carcinoma, where it interacts with MCT4 and its obligate chaperone Basigin. TMPRSS11B catalytic activity promotes Basigin solubilization, which enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis.

Original languageEnglish (US)
JournalCell Reports
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

CD147 Antigens
Metabolism
Lactic Acid
Lung Neoplasms
Peptide Hydrolases
Squamous Cell Carcinoma
Growth
Lung
Tumors
Neoplasms
Monocarboxylic Acid Transporters
Carcinogenesis
Cells
Enzyme Therapy
Serine Proteases
Ports and harbors
Metabolic Networks and Pathways
Catalysis
Non-Small Cell Lung Carcinoma
Catalyst activity

Keywords

  • Basigin
  • CRISPR-mediated genome editing
  • glycolytic metabolism
  • lactate export
  • lung cancer
  • lung squamous cell carcinoma
  • MCT4
  • TMPRSS11B
  • transmembrane serine protease
  • transposon mutagenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism. / Updegraff, Barrett L.; Zhou, Xiaorong; Guo, Yabin; Padanad, Mahesh S.; Chen, Pei Hsuan; Yang, Chendong; Sudderth, Jessica; Rodriguez-Tirado, Carla; Girard, Luc; Minna, John D; Mishra, Prashant; DeBerardinis, Ralph J; O'Donnell-Mendell, Kathryn A.

In: Cell Reports, 01.01.2018.

Research output: Contribution to journalArticle

Updegraff, Barrett L. ; Zhou, Xiaorong ; Guo, Yabin ; Padanad, Mahesh S. ; Chen, Pei Hsuan ; Yang, Chendong ; Sudderth, Jessica ; Rodriguez-Tirado, Carla ; Girard, Luc ; Minna, John D ; Mishra, Prashant ; DeBerardinis, Ralph J ; O'Donnell-Mendell, Kathryn A. / Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism. In: Cell Reports. 2018.
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abstract = "Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells. Updegraff et al. show that transmembrane protease TMPRSS11B is upregulated in lung squamous cell carcinoma, where it interacts with MCT4 and its obligate chaperone Basigin. TMPRSS11B catalytic activity promotes Basigin solubilization, which enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis.",
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AU - Updegraff, Barrett L.

AU - Zhou, Xiaorong

AU - Guo, Yabin

AU - Padanad, Mahesh S.

AU - Chen, Pei Hsuan

AU - Yang, Chendong

AU - Sudderth, Jessica

AU - Rodriguez-Tirado, Carla

AU - Girard, Luc

AU - Minna, John D

AU - Mishra, Prashant

AU - DeBerardinis, Ralph J

AU - O'Donnell-Mendell, Kathryn A

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Y1 - 2018/1/1

N2 - Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells. Updegraff et al. show that transmembrane protease TMPRSS11B is upregulated in lung squamous cell carcinoma, where it interacts with MCT4 and its obligate chaperone Basigin. TMPRSS11B catalytic activity promotes Basigin solubilization, which enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis.

AB - Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells. Updegraff et al. show that transmembrane protease TMPRSS11B is upregulated in lung squamous cell carcinoma, where it interacts with MCT4 and its obligate chaperone Basigin. TMPRSS11B catalytic activity promotes Basigin solubilization, which enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis.

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KW - transmembrane serine protease

KW - transposon mutagenesis

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