Fumarate hydratase inhibits non-small cell lung cancer metastasis via inactivation of AMPK and upregulation of DAB2

Anupama Vadhan; Yi-Fang Yang; Yun-Ming Wang; Pang-Yu Chen; Shey-Cherng Tzou; Kuang-Hung Cheng; Stephen Chu-Sung Hu; Tian-Lu Cheng; Yen-Yun Wang; Shyng-Shiou F Yuan

doi:10.3892/ol.2022.13627

Fumarate hydratase inhibits non-small cell lung cancer metastasis via inactivation of AMPK and upregulation of DAB2

Oncol Lett. 2022 Dec 9;25(1):42. doi: 10.3892/ol.2022.13627. eCollection 2023 Jan.

Authors

Anupama Vadhan¹, Yi-Fang Yang², Yun-Ming Wang^{3

4

5}, Pang-Yu Chen¹, Shey-Cherng Tzou^{6

7

8}, Kuang-Hung Cheng^{9

10}, Stephen Chu-Sung Hu^{11

12}, Tian-Lu Cheng^{8

13}, Yen-Yun Wang^{5

14}, Shyng-Shiou F Yuan^{1

3

14

15

16}

Affiliations

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
² Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, R.O.C.
³ Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan, R.O.C.
⁴ Department of Biomedical Science and Environmental Biology, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
⁵ School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
⁶ Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan, R.O.C.
⁷ Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan, R.O.C.
⁸ Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
⁹ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C.
¹⁰ Department of Medical Laboratory Science and Biotechnology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
¹¹ Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
¹² Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
¹³ Department of Biomedical and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
¹⁴ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
¹⁵ Department of Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
¹⁶ Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.

Abstract

Lung cancer is one of the leading causes of cancer mortality worldwide. As it is often first diagnosed only when cancer metastasis has already occurred, the development of effective biomarkers for the risk prediction of cancer metastasis, followed by stringent monitoring and the early treatment of high-risk patients, is essential for improving patient survival. Cancer cells exhibit alterations in metabolic pathways that enable them to maintain rapid growth and proliferation, which are quite different from the metabolic pathways of normal cells. Fumarate hydratase (FH, fumarase) is a well-known tricarboxylic acid cycle enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. The current study sought to investigate the relationship between FH expression levels and the outcome of patients with lung cancer. FH was knocked down in lung cancer cells using shRNA or overexpressed using a vector, and the effect on migration ability was assessed. Furthermore, the role of AMP-activated protein kinase (AMPK) phosphorylation and disabled homolog 2 in the underlying mechanism was investigated using an AMPK inhibitor approach. The results showed that in lung cancer tissues, low FH expression was associated with lymph node metastasis, tumor histology and recurrence. In addition, patients with low FH expression exhibited a poor overall survival in comparison with patients having high FH expression. When FH was overexpressed in lung cancer cells, cell migration was reduced with no effect on cell proliferation. Furthermore, the level of phosphorylated (p-)AMPK, an energy sensor molecule, was upregulated when FH was knocked down in lung cancer cells, and the inhibition of p-AMPK led to an increase in the expression of disabled homolog 2, a tumor suppressor protein. These findings suggest that FH may serve as an effective biomarker for predicting the prognosis of lung cancer and as a therapeutic mediator.

Keywords: AMPK; disabled homolog 2; fumarate hydratase; lung cancer; migration.

Grants and funding

This study was funded by grants from the Ministry of Science and Technology (grant nos. MOST110-2314-B-037-129, MOST110-2314-B-037-084 and MOST110-2314-B-037-058) and the Center for Intelligent Drug Systems and Smart Bio-devices (IDS²B) from the Featured Areas Research Center Program within the framework of Higher Education Sprout Project by the Ministry of Education, Taiwan. This study was also supported by grants from Kaohsiung Medical University Hospital [grant nos. KMUH110-0R43 and KMUH-DK(A)110001] and Kaohsiung Medical University [grant nos. KMU-DK108005, NYTU-KMU-109-IF-01, NYCU-KMU-111-I002 and KMU-DK(A)111005].