1. Academic Validation
  2. Sulforaphane reverses the enhanced NSCLC metastasis by regulating the miR-7-5p/c-Myc/LDHA axis in the acidic tumor microenvironment

Sulforaphane reverses the enhanced NSCLC metastasis by regulating the miR-7-5p/c-Myc/LDHA axis in the acidic tumor microenvironment

  • Phytomedicine. 2024 Oct:133:155874. doi: 10.1016/j.phymed.2024.155874.
Zhiqiang Shi 1 Huiyan Zeng 2 Bingquan Zhao 1 Chen Zeng 1 Fan Zhang 1 Zhongqiu Liu 3 Hiu Yee Kwan 4 Tao Su 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
  • 2 Department of Endocrinology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
  • 3 State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau. Electronic address: liuzq@gzucm.edu.cn.
  • 4 Centre for Cancer & Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, PR China. Electronic address: hykwan@hkbu.edu.hk.
  • 5 State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. Electronic address: sutao@gzucm.edu.cn.
Abstract

Background: The presence of distant metastasis at the time of initial diagnosis is a prevalent issue in non-small cell lung Cancer (NSCLC), affecting around 30-40 % of the patients. Acidic tumor microenvironment (TME) provides favorable conditions that increase the invasiveness and aggressiveness of NSCLC. The activity of the glycolytic enzyme Lactate Dehydrogenase (LDHA) increases intracellular lactate accumulation, which creates an acidic TME. However, it is not yet known whether LDHA is involved in enhancing the metastatic potential of NSCLC and if LDHA is a druggable therapeutic target for NSCLC.

Purpose: We aimed to investigate the molecular mechanisms underlying the enhanced NSCLC metastasis in acidic TME, and to explore whether sulforaphane (SFN), an active compound in Raphani Semen, can serve as a LDHA inhibitor to inhibit NSCLC metastasis in the acidic TME.

Methods: To mimic the acidic TME, NSCLC cells were cultured in acidic medium (pH 6.6), normal medium (pH 7.4) served as control. Western blotting, bioinformatic analysis, luciferase assay and rescue experiments were used to explore the mechanism and investigate the anti-metastatic effect of SFN both in vitro and in vivo.

Results: Acidic environment increases the expression of LDHA which in turn increases the production of lactic acid that contributes to the acidity of TME. Interestingly, elevated LDHA expression results from increased c-Myc expression, which transactivates LDHA. c-Myc expression is directly regulated by miR-7-5p. In vitro study shows that overexpression of miR-7-5p reverses the acidic pH-enhanced c-Myc and LDHA expressions and also abolishes the enhanced NSCLC cell migration. More importantly, SFN significantly inhibits NSCLC growth and metastasis by reducing lactate production via the miR-7-5p/c-Myc/LDHA axis. Besides, it also regulates the expressions of Monocarboxylate Transporter 1 (MCT1) and MCT4 that transport lactate across cell membrane.

Conclusions: The miR-7-5p/c-Myc/LDHA axis is involved in the enhanced NSCLC metastasis in the acidic TME. SFN, a novel LDHA inhibitor, reduces lactate production by targeting the miR-7-5p/c-Myc/LDHA axis, and hence inhibits NSCLC metastasis. Our findings not only delineate a novel mechanism, but also support the clinical translation of SFN as a novel therapeutic agent for treating metastatic NSCLC.

Keywords

Acidic tumor microenvironment; LDHA; Non-small cell lung cancer; Sulforaphane; miR-7-5p/c-Myc/LDHA axis.

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