PPARγ sumoylation-mediated lipid accumulation in lung cancer.

Ai N.H Phan,Jaekyoung Son,Se-Young Jo,Min-Kyu Kim,Tuyen N.M Hua,Young-Ah Suh,Jong-Whan Choi,Yangsik Jeong,Hyun-Won Kim,Vu T.A Vo

doi:10.18632/oncotarget.19700

Ai N.H Phan, Jaekyoung Son + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.19700

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Journal: Oncotarget	Publication Date: Jul 31, 2017
Citations: 16	License type: cc-by

Affiliation: Yonsei University, Asan Medical Center

Abstract

Metabolic reprogramming as a crucial emerging hallmark of cancer is critical for tumor cells to maintain cellular bioenergetics, biosynthesis and reduction/oxidation (REDOX) balance. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor regulating transcription of diverse gene sets involved in inflammation, metabolism, and suppressing tumor growth. Thiazolidinediones (TZDs), as selective PPARγ ligands, are insulin-sensitizing drugs widely prescribed for type 2 diabetic patients in the clinic. Here, we report that sumoylation of PPARγ couples lipid metabolism to tumor suppressive function of the receptor in lung cancer. We found that ligand activation of PPARγ dramatically induced de novo lipid synthesis as well as fatty acid beta (β)-oxidation in lung cancer both in vitro and in vivo. More importantly, it turns out that PPARγ regulation of lipid metabolism was dependent on sumoylation of PPARγ. Further biochemical analysis revealed that PPARγ-mediated lipid synthesis depletes nicotinamide adenine dinucleotide phosphate (NADPH), consequently resulting in increased mitochondrial reactive oxygen species (ROS) level that subsequently disrupted REDOX balance in lung cancer. Therefore, liganded PPARγ sumoylation is not only critical for cellular lipid metabolism but also induces oxidative stress that contributes to tumor suppressive function of PPARγ. This study provides an important insight of future translational and clinical research into targeting PPARγ regulation of lipid metabolism in lung cancer patients accompanying type 2 diabetes.

Highlights

Lung cancer is the leading cause of cancer death with nearly 1.8 million diagnoses and 1.6 million deaths worldwide every year [1]
Metabolic rewiring during oncogene-driven tumor progression is believed to be a crucial biochemical adaptation process for lung cancer initiation as well as progression, and tumors once established become dependent on the reprogrammed metabolic pathways for maintaining the malignancy and aggressiveness [5]
Combined targeting oncogenic drivers and metabolic dependency such as bioenergetics, biosynthesis, and REDOX balance would be opted as a potential therapeutic approach for lung cancer in the clinical setting

Summary

Introduction

Lung cancer is the leading cause of cancer death with nearly 1.8 million diagnoses and 1.6 million deaths worldwide every year [1]. Most patients diagnosed with advanced lung cancer accompany poor prognosis, and standard therapies such as radio-chemotherapy or targeted treatment confer little benefit for the survival rate [2, 3].recently, different oncologic features between patients even with the same histologic type of tumors have led to personalized genomic screening to identify the most effective, individualized treatment option that matches each patient [4]. Increasing advances in diagnosis and standard therapy have been achieved, treatment and prevention of lung cancer are unsatisfactory that requires a better understanding of the molecular mechanisms for the cancer progression. Increasing tumor vulnerability by targeting cancer metabolism, especially REDOX balance would become a potential adjuvant scheme to improve therapeutic efficacy for currently available anticancer treatment options in the clinic [9, 10]

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