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PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression

Oncogene (2024)Cite this article

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Abstract

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

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Fig. 1: PDIA2 expression is associated with prostate tumor progression and venous thrombosis events.
Fig. 2: PDIA2 promotes androgen-independent PCa tumor progression and thrombogenicity through PCa-derived extracellular vehicles(EVs).
Fig. 3: Androgen deprivation promotes PDIA2 trafficking in prostate cancer cells.
Fig. 4: PDIA2 active tissue factors (TF) on PCa-derived EVs.
Fig. 5: EVs bearing active TF activates AR through c-Src kinase for prostate cancer progression.
Fig. 6: PDIA2 expression is controlled by androgen-independent AR signaling in CRPC.
Fig. 7: Blocking PDIA2 activity inhibits CRPC progression and PCa-associated thrombosis.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work is supported by the National Nature Science Foundation of China (82170511 to YL and 82370495 to LZ) and National Nature Science Foundation of Shanghai City (20ZR1471800 to YL) and China postdoctoral science foundation (2022M712111 to YL) and National VTE Prevention and Control Research Fund Project Special Excellence Project (Y031 to LL).

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Author notes

  1. These authors contributed equally: Yinan Li, Lei Lv, Meng Ye.

  2. These authors jointly supervised this work: Jianjun Sha, Xuesen Dong, Lan Zhang.

Authors and Affiliations

  1. Department of Vascular Surgery, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

    Yinan Li, Lei Lv, Meng Ye, Yuli Wang, Weilun Wang, Shuofei Yang, Qihong Ni, Jiaquan Chen, Xiangjiang Guo, Yiping Zhao, Guanhua Xue & Lan Zhang

  2. Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Ning Xie, Ladan Fazli & Xuesen Dong

  3. Department of Urology, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

    Jianjun Sha

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Contributions

Concept and design: Li Y, Zhang L, Dong X, Sha J, Acquisition of data: Li Y, Lv L, Ye M. Analysis and interpretation of data: Li Y, Lv L, Ye M, Sha J, Drafting the manuscript: Li Y, Zhang L, Dong X, Critical revision of the manuscript: Zhang L, Dong X. Statistically analysis: Li Y, Lv L, Ye M. Obtain funding: Li Y, Zhang L, Lv L. Administrative, technical or material support: Ning X, Ladan F, Wang Y, Wang W, Yang S, Ni Q, Chen J, Guo X, Zhao Y, Xue G.

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Correspondence to Jianjun Sha, Xuesen Dong or Lan Zhang.

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All procedures were approved by the research ethics committee of the Renji Hospital (LY2023-027-A). All patients included in this research provided written informed consent.

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Li, Y., Lv, L., Ye, M. et al. PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression. Oncogene (2024). https://doi.org/10.1038/s41388-024-03024-1

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