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

doi:10.1038/s41388-022-02410-x

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 journal › Article › peer-review

11 Scopus citations

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 language	English
Pages (from-to)	4042-4054
Number of pages	13
Journal	Oncogene
Volume	41
Issue number	33
DOIs	https://doi.org/10.1038/s41388-022-02410-x
State	Published - Aug 12 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

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. 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.

Funders	Funder number
University of Florida Medicinal Chemistry Mass Spectrometry Support
National Institutes of Health (NIH)	R01CA193286
National Childhood Cancer Registry – National Cancer Institute	R01CA193278
Cancer Center, University of Florida Health
National Natural Science Foundation of China (NSFC)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

Access to Document

10.1038/s41388-022-02410-x

Cite this

Bian, T., Wang, Y., Botello, J. F., Hu, Q., Jiang, Y., Zingone, A., Ding, H., Wu, Y., Zahra Aly, F., Salloum, R. G., Warren, G., Huo, Z., Ryan, B. M., Jin, L., & Xing, C. (2022). LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner. Oncogene, 41(33), 4042-4054. https://doi.org/10.1038/s41388-022-02410-x

@article{02e2408dfe06441cb6ef3eaf72c6a126,

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

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{\textquoteright} 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.].",

author = "Tengfei Bian and Yuzhi Wang and Botello, \{Jordy F.\} and Qi Hu and Yunhan Jiang and Adriana Zingone and Haocheng Ding and Yougen Wu and \{Zahra Aly\}, F. and Salloum, \{Ramzi G.\} and Graham Warren and Zhiguang Huo and Ryan, \{Br{\'i}d M.\} and Lingtao Jin and Chengguo Xing",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = aug,

day = "12",

doi = "10.1038/s41388-022-02410-x",

language = "English",

volume = "41",

pages = "4042--4054",

number = "33",

}

Bian, T, Wang, Y, Botello, JF, Hu, Q, Jiang, Y, Zingone, A, Ding, H, Wu, Y, Zahra Aly, F, Salloum, RG, Warren, G, Huo, Z, Ryan, BM, Jin, L & Xing, C 2022, 'LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner', Oncogene, vol. 41, no. 33, pp. 4042-4054. https://doi.org/10.1038/s41388-022-02410-x

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

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.].

UR - https://www.scopus.com/pages/publications/85134338279

UR - https://www.scopus.com/pages/publications/85134338279#tab=citedBy

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 -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this