LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner

Tengfei Bian, Yuzhi Wang, Jordy F. Botello, Qi Hu, Yunhan Jiang, Adriana Zingone, Haocheng Ding, Yougen Wu, F. Zahra Aly, Ramzi G. Salloum, Graham Warren, Zhiguang Huo, Bríd M. Ryan, Lingtao Jin, Chengguo Xing

Research output: Contribution to journalArticlepeer-review

Abstract

LKB1 loss of function is one key oncogenic event in lung cancer. Clinical data suggest that LKB1 loss of function is associated with patients’ smoking status. The responsible ingredients and molecular mechanisms in tobacco for LKB1 loss of function, however, are not defined. In this study, we reported that NNAL, a major metabolite of a tobacco-specific carcinogen NNK, induces LKB1 phosphorylation and its loss of function via the β-AR/PKA signaling pathway in an isomer-dependent manner in human lung cancer cells. NNAL exposure also resulted in enhanced lung cancer cell migration and chemoresistance in an LKB1-dependent manner. A 120-day NNAL exposure in lung cancer cells, mimicking its chronic exposure among smokers, resulted in more prominent LKB1 phosphorylation, cell migration, and chemoresistance even in the absence of NNAL, indicating the long-lasting LKB1 loss of function although such an effect eventually disappeared after NNAL was removed for two months. These observations were confirmed in a lung cancer xenograft model. More importantly, human lung cancer tissues revealed elevated LKB1 phosphorylation in comparison to the paired normal lung tissues. These results suggest that LKB1 loss of function in human lung cancer could be extended to its phosphorylation, which may be mediated by NNAL from tobacco smoke in an isomer-dependent manner via the β-AR/PKA signaling pathway. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)4042-4054
Number of pages13
JournalOncogene
Volume41
Issue number33
DOIs
StatePublished - Aug 12 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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