2. Academic Validation
  3. Targeting PKD2 aggravates ferritinophagy-mediated ferroptosis via promoting autophagosome-lysosome fusion and enhances efficacy of carboplatin in lung adenocarcinoma

Targeting PKD2 aggravates ferritinophagy-mediated ferroptosis via promoting autophagosome-lysosome fusion and enhances efficacy of carboplatin in lung adenocarcinoma

  • Chem Biol Interact. 2023 Nov 9:110794. doi: 10.1016/j.cbi.2023.110794.
Yong Liu 1,  Zhaofei Pang 2,  Yadong Wang 1,  Jichang Liu 1,  Guanghui Wang 3,  Jiajun Du 4
Affiliations

Affiliations

  • 1 Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
  • 2 Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China; Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 3 Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China; Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
  • 4 Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China; Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Department of Thoracic Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China. Electronic address: [email protected].
PMID: 37951334 DOI: 10.1016/j.cbi.2023.110794
Abstract

Ferroptosis is an iron-dependent cell death and affects efficacies of multiple antitumor regimens, showing a great potential in Cancer therapy. Protein kinase D2 (PKD2) plays a crucial role in regulating necrosis and Apoptosis. However, the relationship of PKD2 and Ferroptosis is still elusive. In this study, we mainly analyzed the roles of PKD2 on Ferroptosis and chemotherapy in lung adenocarcinoma (LUAD). We found PKD2 was highly expressed in LUAD and silencing PKD2 could promote erastin-induced Reactive Oxygen Species (ROS), malondialdehyde (MDA) accumulation, intracellular iron content and LUAD cells death. Mechanistically, augmenting PKD2 could prevent autophagic degradation of ferritin, which could be impaired by bafilomycin A1. We further found that PKD2 overexpression would promote LC3B-II, p62/SQSTM1 accumulation and block autophagosome-lysosome fusion in a TFEB-independent manner, which could be impaired by bafilomycin A1. Bafilomycin A1 stimulation could weaken Ferroptosis promotion by PKD2 abrogation. Silencing ferritin heavy chain-1 (FTH1) could reverse the resistance to Ferroptosis by PKD2 overexpression. Additionally, in vitro and vivo experiments validated PKD2 promoted proliferation, migration and invasion of LUAD cells. PKD2 knockdown or pharmacological inhibition by CRT0066101 could enhance efficacy of carboplatin in LUAD via Ferroptosis and Apoptosis. Collectively, our study revealed that abrogation of PKD2 could aggravate ferritinophagy-mediated Ferroptosis by promoting autophagosome-lysosome fusion and enhance efficacy of carboplatin in LUAD. Targeting PKD2 to induce Ferroptosis may be a promising strategy for LUAD therapy.

Keywords

Autophagy; Ferroptosis; Lung adenocarcinoma; Protein kinase D2; Reactive oxygen species.

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