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Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer

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Abstract

Introduction

Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success.

Methods

In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells.

Results

The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity.

Conclusions

Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

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Abbreviations

ECM:

Extracellular matrix

GAGs:

Glycosaminoglycans

MCT1:

Monocarboxylate transporter

PEC:

Polyacrylic complex

PFK-1:

Phosphofructokinase-1

ROS:

Reactive oxygen species

PGC-1α:

Transcription coactivator peroxisome proliferator-activated receptor gamma

SOD2:

Manganese superoxide dismutase

SOD1:

Recombinant superoxide dismutase 1

TBST:

Tris-buffered saline with TweenR 20

TCA:

Tricarboxylic acid

3D:

Three-dimensional

2D:

Two-dimensional

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Acknowledgments

This work was supported by the Japan Society for the Promotion of Science under Grants-in-Aid for Scientific Research (S; No. 17H06146). Xiaorong Fu acknowledges the support of the China Scholarship Council (Grant Number 201906050131).

Author Contributions

XF: Investigation, Methodology, Visualization, Writing-original draft, Writing- review & editing. YK: Resources, Investigation, Methodology, Writing-review & editing. YT: Resources, Writing-review & editing. GS: Resources, Writing- review & editing. YJ: Conceptualization, Supervision, Writing- original draft, Writing- review & editing, Funding acquisition.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conflict of interest

X.F., Y.K., Y.T., G.S., and Y.J. declare that they have no financial, professional, or personal conflict of interest.

Ethical Approval

No animal or human studies were carried out by the authors of this article.

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Authors and Affiliations

  1. Department of Micro-Nano Mechanical Science and Engineering, Graduate School of Engineering, Nagoya University, Nagoya City, Aichi State, Japan

    Xiaorong Fu, Yasuhiro Kimura, Yuhki Toku & Yang Ju

  2. College of Bioengineering, Chongqing University, Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing, 400030, People’s Republic of China

    Guanbin Song

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  1. Xiaorong Fu
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Correspondence to Yang Ju.

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Fu, X., Kimura, Y., Toku, Y. et al. Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer. Cel. Mol. Bioeng. 16, 69–80 (2023). https://doi.org/10.1007/s12195-022-00751-x

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