L1CAM mediates neuroendocrine phenotype acquisition in prostate cancer cells

Chia-Ling Hsieh^{1

2

3}, Anh Duy Do^{4

5}, Chia-Yen Hsueh¹, Mafewu Olga Raboshakga^{4

6}, Tran Ngoc Thanh⁵, Tran Tien Tai⁵, Hsing-Jien Kung^{7

8}, Shian-Ying Sung^{1

3

4

9}

Affiliations

¹ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
² General Clinical Research Center, Chung Shan Medical University Hospital, Taichung, Taiwan.
³ Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴ International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁵ Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
⁶ Department of Pre-Clinical Sciences, University of Limpopo, Sovenga, South Africa.
⁷ Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, University of California Davis Cancer Centre, Sacramento, California, USA.
⁸ Taipei Medical University, Taipei, Taiwan.
⁹ Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

PMID: 39154281
DOI: 10.1002/pros.24782

L1CAM mediates neuroendocrine phenotype acquisition in prostate cancer cells

Chia-Ling Hsieh et al. Prostate. 2024 Dec.

. 2024 Dec;84(16):1434-1447.

doi: 10.1002/pros.24782. Epub 2024 Aug 18.

Authors

Chia-Ling Hsieh^{1

2

3}, Anh Duy Do^{4

5}, Chia-Yen Hsueh¹, Mafewu Olga Raboshakga^{4

6}, Tran Ngoc Thanh⁵, Tran Tien Tai⁵, Hsing-Jien Kung^{7

8}, Shian-Ying Sung^{1

3

4

9}

Affiliations

¹ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
² General Clinical Research Center, Chung Shan Medical University Hospital, Taichung, Taiwan.
³ Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴ International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
⁵ Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
⁶ Department of Pre-Clinical Sciences, University of Limpopo, Sovenga, South Africa.
⁷ Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, University of California Davis Cancer Centre, Sacramento, California, USA.
⁸ Taipei Medical University, Taipei, Taiwan.
⁹ Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.

PMID: 39154281
DOI: 10.1002/pros.24782

Abstract

Background: A specific type of prostate cancer (PC) that exhibits neuroendocrine (NE) differentiation is known as NEPC. NEPC has little to no response to androgen deprivation therapy and is associated with the development of metastatic castration-resistant PC (CRPC), which has an extremely poor prognosis. Our understanding of genetic drivers and activated pathways in NEPC is limited, which hinders precision medicine approaches. L1 cell adhesion molecule (L1CAM) is known to play an oncogenic role in metastatic cancers, including CRPC. However, the impact of L1CAM on NEPC progression remains elusive.

Methods: L1CAM expression level was investigated using public gene expression databases of PC cohorts and patient-derived xenograft models. L1CAM knockdown was performed in different PC cells to study in vitro cell functions. A subline of CRPC cell line CWR22Rv1 was established after long-term exposure to abiraterone to induce NE differentiation. The androgen receptor-negative cell line PC3 was cultured under the tumor sphere-forming condition to enrich cancer stemness features. Several oxidative stress inducers were tested on PC cells to observe L1CAM-mediated gene expression and cell death.

Results: L1CAM expression was remarkably high in NEPC compared to CRPC or adenocarcinoma tumors. L1CAM was also correlated with NE marker expressions and associated with the adenocarcinoma-to-NEPC progression in gene expression databases and CRPC cells with NE differentiation. L1CAM also promoted cancer stemness and NE phenotypes in PC3 cells under cancer stemness enrichment. L1CAM was also identified as a reactive oxygen species-induced gene, by which L1CAM counteracted CRPC cell death triggered by ionizing radiation.

Conclusions: Our results unveiled a new role of L1CAM in the acquisition of the NE phenotype in PC, contributing to the NE differentiation-related therapeutic resistance of CRPC.

Keywords: L1 cell adhesion molecule; NEPC; cancer stemness; castration‐resistant prostate cancer; neuroendocrine differentiation; oxidative stress.

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References

REFERENCES

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L1CAM mediates neuroendocrine phenotype acquisition in prostate cancer cells

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L1CAM mediates neuroendocrine phenotype acquisition in prostate cancer cells

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