Gankyrin-mediated interaction between cancer cells and tumor-associated macrophages facilitates prostate cancer progression and androgen deprivation therapy resistance

ABSTRACT

Increasing evidence reveals that the interaction between tumor cells and tumor-associated macrophages (TAMs) facilitates the progression of prostate cancer, but the related mechanisms remained unclear. This study determined how gankyrin, a component of the 19S regulatory complex of the 26S proteasome, regulates the progression and androgen deprivation therapy (ADT) resistance of prostate cancer through tumor cell–TAM interactions. In vitro functional experiments and in vivo subcutaneous tumor models were used to explore the biological role and molecular mechanisms of gankyrin in prostate cancer cell–TAM interactions. 234 prostate cancer patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin through immunohistochemistry (IHC) and statistical analyses, and high gankyrin expression was correlated with poor prognosis. In addition, gankyrin facilitated the progression and ADT resistance of prostate cancer. Mechanistically, gankyrin recruited and upregulated non–POU-domain–containing octamer-binding protein (NONO) expression, resulting in increased androgen receptor (AR) expression. AR then bound to the high-mobility group box 1 (HMGB1) promoter to trigger HMGB1 transcription, expression, and secretion. Moreover, HMGB1 was found to promote the recruitment and activation of TAMs, which secrete IL-6 to reciprocally promote prostate cancer progression, ADT resistance and gankyrin expression via STAT3, resulting in formation of a gankyrin/NONO/AR/HMGB1/IL-6/STAT3 positive feedback loop. Furthermore, targeting the interaction between tumor cells and TAMs by blocking this loop inhibited ADT resistance in a tumor xenograft model. Taken together, the data show that gankyrin serves as a reliable prognostic indicator and therapeutic target for prostate cancer patients.

KEYWORDS:

• Tumor-associated macrophages
• gankyrin
• prostate cancer
• androgen deprivation therapy
• tumor progression

Abbreviations

CRPC: Castration resistant prostate cancer; TAM: tumor-associated macrophage; CHIP: Chromatin immunoprecipitation; ADT: Androgen deprivation therapy; PSA: Prostate Specific Antigen; NONO:non–POU-domain–containing octamer-binding protein HMGB1: High Mobility Group Box 1; TME: Tumor microenvironment; ELISA: Enzyme linked immune sorbent assay; GS: Gleason score; BPH: Benign prostatic hyperplasia; BCR: Biochemical recurrence; DFS: Disease free survival; CM: conditioned medium; ROC: receiver operating characteristics; GEO: Gene Expression Omnibus

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplemental materials.

Disclosure statement

The authors have declared that no competing interest exists

Author contributions

Guang Peng, Chao Wang, Yuquan Jiang, Sishun Gan, and Xu Gao designed and organize the implementation of the project; Chao Wang, Guang Peng, Hongru Wang, Min Qu, Keqin Dong, Yongwei Yu collected and assembled the data. Chao Wang, Guang Peng, Hongru Wang, Min Qu, and Keqin Dong analyzed the data; Guang Peng and Chao Wang wrote the manuscript. The final paper was approved by all of the authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2173422

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No. 82173357, 81773154), Shanghai Natural Science Foundation (No. 20ZR1449600), Pudong New Area Science and technology development fund special fund for people’s livelihood Research (medical and health) (PKJ2019-Y19), The Top-level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03), Construction of clinical peak discipline of Shanghai Pudong New Area Health Committee (PYWgf2021-06), Shanghai Sailing Program (19YF1447000), the Science and Technology Foundation of the Health Commission of Guizhou province (gzwkj2022-102).