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Kindlin-2 links mechano-environment to proline synthesis and tumor growth

Ling Guo1, Chunhong Cui2, Kuo Zhang2

  • 1Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Department of Biology and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. guol@sustc.edu.cn.

Nature Communications
|February 21, 2019
PubMed

Insights

Stiff environments boost cell growth by increasing proline synthesis via a kindlin-2 and PYCR1 interaction. Targeting this pathway inhibits lung cancer growth.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Oncology

Background:

  • Cellular metabolism is significantly affected by the mechanical properties of the cellular environment.
  • The protein kindlin-2 plays a role in cellular responses to mechanical cues.

Purpose of the Study:

  • To investigate the role of kindlin-2 in mediating the effects of the mechano-environment on cell metabolism.
  • To explore the potential of targeting the kindlin-2-PYCR1 pathway in cancer therapy.

Main Methods:

  • Mitochondrial localization studies of kindlin-2.
  • Analysis of pyrroline-5-carboxylate reductase 1 (PYCR1) enzyme activity and proline synthesis.
  • Assessment of reactive oxygen species (ROS) production and apoptosis.
  • In vivo studies using a lung adenocarcinoma model.

Main Results:

  • Kindlin-2 translocates to mitochondria upon extracellular matrix (ECM) stiffening, interacting with PYCR1.
  • ECM stiffening increases PYCR1 levels, proline synthesis, and cell proliferation.
  • Kindlin-2 depletion reduces PYCR1, increases ROS and apoptosis, and blocks proliferation.
  • In lung adenocarcinoma, kindlin-2 and PYCR1 are upregulated; kindlin-2 ablation inhibits tumor growth and mortality.

Conclusions:

  • A novel mechanoresponsive kindlin-2-PYCR1 complex links the mechano-environment to proline metabolism and cell signaling.
  • This complex represents a potential therapeutic target for inhibiting tumor growth, particularly in lung adenocarcinoma.

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