Endoglin as a predictive biomarker for pemetrexed sensitivity in non-small-cell lung cancer: a cellular study

Ching-Yuan Cheng; Wen-Chen Chuang; Ching-Pin Lin; Che-Hsing Li; Hui-Yi Chang; Wen-Jun Wu; Ming-Fang Wu; Jiunn-Liang Ko

doi:10.1007/s00280-024-04734-9

Endoglin as a predictive biomarker for pemetrexed sensitivity in non-small-cell lung cancer: a cellular study

Cancer Chemother Pharmacol. 2025 Jan 10;95(1):20. doi: 10.1007/s00280-024-04734-9.

Authors

Ching-Yuan Cheng^#^{1

2

3}, Wen-Chen Chuang^#^{4

5}, Ching-Pin Lin^{4

6}, Che-Hsing Li^{7

8}, Hui-Yi Chang⁵, Wen-Jun Wu^{4

5}, Ming-Fang Wu^{9

10

11}, Jiunn-Liang Ko^{12

13

14}

Affiliations

¹ Division of Thoracic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, 500209, Taiwan.
² Division of Thoracic Surgery, Department of Surgery, Yunlin Christian Hospital, Yunlin, 648106, Taiwan.
³ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, 40227, Taiwan.
⁴ School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.
⁵ Institute of Medicine, Chung-Shan Medical University, Taichung, 40201, Taiwan.
⁶ Division of Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan.
⁷ Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, 77030, USA.
⁸ Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
⁹ Institute of Medicine, Chung-Shan Medical University, Taichung, 40201, Taiwan. mfwu0111@gmail.com.
¹⁰ Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan. mfwu0111@gmail.com.
¹¹ CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 40201, Taiwan. mfwu0111@gmail.com.
¹² Institute of Medicine, Chung-Shan Medical University, Taichung, 40201, Taiwan. jlko@csmu.edu.tw.
¹³ Divisions of Medical Oncology and Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan. jlko@csmu.edu.tw.
¹⁴ CSMU Lung Cancer Research Center, Chung Shan Medical University, Taichung, 40201, Taiwan. jlko@csmu.edu.tw.

^# Contributed equally.

PMID: 39792181
DOI: 10.1007/s00280-024-04734-9

Abstract

Objective: Based on our previous research, which demonstrated that elevated plasma endoglin (ENG) levels in lung cancer patients were associated with a better prognosis, increased sensitivity to pemetrexed, and enhanced tumor suppression, this study aims to validate these findings at the cellular level. The focus is on membrane and extracellular ENG and their influence on drug response and tumor cell behavior in non-small cell lung cancer (NSCLC) cells.

Methods: The correlation between ENG expression and pemetrexed-induced cytotoxicity in eight human non-squamous subtype NSCLC cell lines was analyzed. ENG in A549 and H1975 cells was knocked down using shRNA. MTT assay, cell cycle assay, western blot analysis, and boyden chamber assay were used to detect the effect of ENG on pemetrexed-induced cytotoxicity, cell cycle distribution, and cell migration.

Results: The expression of membrane ENG was positively correlated with pemetrexed-induced cytotoxicity in human NSCLC cells. Compared to pemetrexed-sensitive A549 cells, the A549/a400 (pemetrexed-resistant subline) cells exhibited a reduced accumulation of cells in the S phase, making them less susceptible to cell death. ENG knockdown also alleviated pemetrexed-induced S phase arrest and regulated G1/S phase-related proteins (p53, p21, CDK2, and Cyclin A). Additionally, co-treatment with recombinant ENG enhanced pemetrexed-induced migration inhibition in the sensitive cel1 line and cytotoxicity in the resistance cell line.

Conclusion: The present results strengthened our prior clinical findings, showing that higher membrane ENG expression enhances pemetrexed-induced cytotoxicity and S phase arrest, which may involve the ENG-p21 pathway. Additionally, microenvironmental ENG enhanced the anti-migration of pemetrexed. These findings highlight the potential of ENG as a biomarker and therapeutic target, opening new avenues to improve the outcomes of non-squamous cell NSCLC treatment.

Keywords: Biomarker; Cell cycle; Endoglin; Metastasis; Non-small cell lung cancer; Pemetrexed.

Abstract

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