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  3. Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression

Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression

  • Nat Commun. 2024 Jun 8;15(1):4909. doi: 10.1038/s41467-024-49199-9.
Hyun-Ji Jang # 1,  Hye-Young Min # 1 2,  Yun Pyo Kang 3,  Hye-Jin Boo 1 4,  Jisung Kim 1,  Jee Hwan Ahn 1 5,  Seung Ho Oh 3,  Jin Hwa Jung 6,  Choon-Sik Park 7,  Jong-Sook Park 7,  Seog-Young Kim 6 8,  Ho-Young Lee 9 10 11
Affiliations

Affiliations

  • 1 Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
  • 4 Department of Histology, College of Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
  • 5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 6 PET core, Convergence Medicine Research Center, Asan Medical Center, Seoul, 05505, Republic of Korea.
  • 7 Soonchunhyang University Bucheon Hospital, Bucheon-si, Gyeonggi-do, 14584, Republic of Korea.
  • 8 Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 9 Creative Research Initiative Center for concurrent control of emphysema and lung cancer, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
  • 10 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
  • 11 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea. hylee135@snu.ac.kr.
  • # Contributed equally.
PMID: 38851766 DOI: 10.1038/s41467-024-49199-9
Abstract

Tobacco smoking (TS) is implicated in lung Cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung Cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates Insulin Receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/Insulin Receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.

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