TY - JOUR
T1 - LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner
AU - Bian, Tengfei
AU - Wang, Yuzhi
AU - Botello, Jordy F.
AU - Hu, Qi
AU - Jiang, Yunhan
AU - Zingone, Adriana
AU - Ding, Haocheng
AU - Wu, Yougen
AU - Zahra Aly, F.
AU - Salloum, Ramzi G.
AU - Warren, Graham
AU - Huo, Zhiguang
AU - Ryan, Bríd M.
AU - Jin, Lingtao
AU - Xing, Chengguo
N1 - Funding Information:
The work was partly supported by grants from the National Institute of Health (R01CA193286) to CX, the Harry T. Mangurian Jr. Foundation to CX, College of Pharmacy Frank Duckworth Endowment to CX, University of Florida Health Cancer Center Startup fund to CX, and University of Florida Medicinal Chemistry Mass Spectrometry Support to CX. Y Wu was supported by a scholarship from the National Science Foundation of China. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. We also acknowledge the National Cancer Institute for providing PLCO information used in this manuscript. We would like to thank Sreekanth C. Narayanapillai, Santanu Hati, and Pedro Corral for the assistance with sample collection and characterization. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
The work was partly supported by grants from the National Institute of Health (R01CA193286) to CX, the Harry T. Mangurian Jr. Foundation to CX, College of Pharmacy Frank Duckworth Endowment to CX, University of Florida Health Cancer Center Startup fund to CX, and University of Florida Medicinal Chemistry Mass Spectrometry Support to CX. Y Wu was supported by a scholarship from the National Science Foundation of China. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. We also acknowledge the National Cancer Institute for providing PLCO information used in this manuscript. We would like to thank Sreekanth C. Narayanapillai, Santanu Hati, and Pedro Corral for the assistance with sample collection and characterization. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/8/12
Y1 - 2022/8/12
N2 - 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.].
AB - 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.].
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UR - http://www.scopus.com/inward/citedby.url?scp=85134338279&partnerID=8YFLogxK
U2 - 10.1038/s41388-022-02410-x
DO - 10.1038/s41388-022-02410-x
M3 - Article
C2 - 35835853
AN - SCOPUS:85134338279
SN - 0950-9232
VL - 41
SP - 4042
EP - 4054
JO - Oncogene
JF - Oncogene
IS - 33
ER -