Garcinol from Garcinia indica Downregulates Cancer Stem-like Cell Biomarker ALDH1A1 in Nonsmall Cell Lung Cancer A549 Cells through DDIT3 Activation

TY - JOUR

T1 - Garcinol from Garcinia indica Downregulates Cancer Stem-like Cell Biomarker ALDH1A1 in Nonsmall Cell Lung Cancer A549 Cells through DDIT3 Activation

AU - Wang, Jinhan

AU - Wang, Liwen

AU - Ho, Chi Tang

AU - Zhang, Kunsheng

AU - Liu, Qiang

AU - Zhao, Hui

N1 - Funding Information: *E-mail: liuqiang@irm-cams.ac.cn. *E-mail: zhaohui@tjcu.edu.cn. ORCID Liwen Wang: 0000-0001-7135-3418 Hui Zhao: 0000-0002-7517-5054 Funding This work was supported by the National Natural Science Foundation of China (nos. 31571832, 31671873, and 31670859); Natural Science Foundation of Tianjin (no. 15KPXM01SF056); Fundamental Research Funds for CAMS & PUMC (nos. 2016ZX310068 and 2016RC310017); Research Funds for the Innovation Team of IRM-CAMS (no. 1650); and Tianjin Innovative Research Team Grant (TD-12-5049). Notes The authors declare no competing financial interest. Publisher Copyright: © 2017 American Chemical Society.

PY - 2017/5/10

Y1 - 2017/5/10

N2 - Nonsmall cell lung cancer (NSCLC) is the predominant type of lung cancer. Patients with NSCLC show high mortality rates because of failure to clean up cancer stem cells (CSCs). The anticancer activity of phytochemical garcinol has been identified in various cancer cell models. However, the effect of garcinol on NSCLC cell lines is still lacking. Of the NSCLC cell lines we tested, A549 cells were the most sensitive to garcinol. Interestingly, Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) was preferentially expressed in A549 cells and downregulated by the addition of garcinol. We also found that garcinol enriched DNA damage-inducible transcript 3 (DDIT3) and then altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in a decreased binding of C/EBPβ to the endogenous ALDH1A1 promoter. Furthermore, garcinol's inhibition of ALDH1A1 was identified in a xenograft mice model. Garcinol repressed ALDH1A1 transcription in A549 cells through alterations in the interaction between DDIT3 and C/EBPβ. Garcinol could be a potential dietary phytochemical candidate for NSCLCs patients whose tumors harbored high ALDH1A1 expression.

AB - Nonsmall cell lung cancer (NSCLC) is the predominant type of lung cancer. Patients with NSCLC show high mortality rates because of failure to clean up cancer stem cells (CSCs). The anticancer activity of phytochemical garcinol has been identified in various cancer cell models. However, the effect of garcinol on NSCLC cell lines is still lacking. Of the NSCLC cell lines we tested, A549 cells were the most sensitive to garcinol. Interestingly, Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) was preferentially expressed in A549 cells and downregulated by the addition of garcinol. We also found that garcinol enriched DNA damage-inducible transcript 3 (DDIT3) and then altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in a decreased binding of C/EBPβ to the endogenous ALDH1A1 promoter. Furthermore, garcinol's inhibition of ALDH1A1 was identified in a xenograft mice model. Garcinol repressed ALDH1A1 transcription in A549 cells through alterations in the interaction between DDIT3 and C/EBPβ. Garcinol could be a potential dietary phytochemical candidate for NSCLCs patients whose tumors harbored high ALDH1A1 expression.

KW - A549 cells

KW - ALDH1A1

KW - garcinol

KW - nonsmall cell lung cancer

KW - phytochemical

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U2 - https://doi.org/10.1021/acs.jafc.7b00346

DO - https://doi.org/10.1021/acs.jafc.7b00346

M3 - Article

C2 - 28420235

SN - 0021-8561

VL - 65

SP - 3675

EP - 3683

JO - Journal of agricultural and food chemistry

JF - Journal of agricultural and food chemistry

IS - 18

ER -