PPARγ/SOD2 Protects Against Mitochondrial ROS-Dependent Apoptosis via Inhibiting ATG4D-Mediated Mitophagy to Promote Pancreatic Cancer Proliferation

Shuang Nie; Zhao Shi; Mengyue Shi; Hongzhen Li; Xuetian Qian; Chunyan Peng; Xiwei Ding; Shu Zhang; Ying Lv; Lei Wang; Bo Kong; Xiaoping Zou; Shanshan Shen

doi:10.3389/fcell.2021.745554

PPARγ/SOD2 Protects Against Mitochondrial ROS-Dependent Apoptosis via Inhibiting ATG4D-Mediated Mitophagy to Promote Pancreatic Cancer Proliferation

Front Cell Dev Biol. 2022 Feb 2:9:745554. doi: 10.3389/fcell.2021.745554. eCollection 2021.

Authors

Shuang Nie^{1

2}, Zhao Shi^{2

3}, Mengyue Shi^{1

2}, Hongzhen Li^{1

2}, Xuetian Qian^{2

3}, Chunyan Peng^{1

2}, Xiwei Ding^{1

2}, Shu Zhang^{1

2}, Ying Lv^{1

2

3}, Lei Wang^{1

2

3}, Bo Kong^{1

2

4}, Xiaoping Zou^{1

2

3}, Shanshan Shen^{1

2

3}

Affiliations

¹ Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
² Nanjing University Institute of Pancreatology, Nanjing, China.
³ Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, China.
⁴ Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Our previous study found that peroxisome proliferator activated receptor gamma (PPARγ) was capable of enhancing glycolysis in PDAC cells. However, whether PPARγ could promote PDAC progression remains unclear. In our present study, PPARγ was positively associated with tumor size and poor prognosis in PDAC patients. Functional assays demonstrated that PPARγ could promote the proliferation of pancreatic cancer cells in vitro and in vivo. Additionally, flow cytometry results showed that PPARγ decreased mitochondrial reactive oxygen species (mitochondrial ROS) production, stabilized mitochondrial membrane potential (MMP) and inhibited cell apoptosis via up-regulating superoxide dismutase 2 (SOD2), followed by the inhibition of ATG4D-mediated mitophagy. Meanwhile, the activation of PPARγ might reduce pancreatic cancer cell stemness to improve PDAC chemosensitivity via down-regulating ATG4D. Thus, these results revealed that PPARγ/SOD2 might protect against mitochondrial ROS-dependent apoptosis via inhibiting ATG4D-mediated mitophagy to promote pancreatic cancer proliferation, further improving PDAC chemosensitivity.

Keywords: ATG4D; PPARγ; SOD2; mitophagy; pancreatic ductal adenocarcinoma.