Phage display screening identifies a prostate specific antigen (PSA)-/lo prostate cancer cell specific peptide to retard castration resistance of prostate cancer

Yi Sui; Rujian Zhu; Wei Hu; Wei Zhang; Hongbo Zhu; Min Gong; Lili Gao; Ting Cao; Tao Tang; Bo Yu; Tao Yang

doi:10.1016/j.tranon.2021.101020

Phage display screening identifies a prostate specific antigen (PSA)^-/lo prostate cancer cell specific peptide to retard castration resistance of prostate cancer

Transl Oncol. 2021 Mar;14(3):101020. doi: 10.1016/j.tranon.2021.101020. Epub 2021 Jan 26.

Authors

Yi Sui¹, Rujian Zhu², Wei Hu², Wei Zhang³, Hongbo Zhu⁴, Min Gong², Lili Gao⁵, Ting Cao⁵, Tao Tang⁶, Bo Yu⁷, Tao Yang⁸

Affiliations

¹ Department of Nutrition, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
² Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
³ Department of Pharmacology, School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
⁴ Department of Pathology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
⁵ Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
⁶ Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁷ Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China. Electronic address: yubo120@hotmail.com.
⁸ Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China. Electronic address: taoyang@tongji.edu.cn.

Abstract

Patients with prostate cancer (PCa) will eventually progress to castrate-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) treatment. Prostate-specific antigen (PSA)^-^/lo cells which harbor self-renewing long-term tumor-propagating cells that can be enriched using ALDH+CD44+α2β1+ and can initiate tumor development may represent a critical source of CRPC cells. Our purpose was to find a peptide that specifically targets PSA^-^/lo PCa cells to retard the development of CRPC. PSA⁺ and PSA^-^/lo cells were successfully separated from LNCaP xenograft tumors after prostate- PSAP-GFP vector infection and FACS. A variety of PSA^-^/lo cells specifically targeting peptide (named as "TAP1" targeted affinity peptide 1) was identified by using phage display library screening. The highest binding rate in TAP1 binding cell subpopulations are identified to be among ALDH⁺CD44⁺CXCR4⁺CD24⁺ cells. TAP1 significantly inhibited PCa growth both in vitro and in vivo. TAP1 significantly improved the anti-proliferation effect of the anti-androgens (Charcoal dextran-stripped serum (CDSS)+Bicalutamide, Enzalutamide) and chemotherapeutic agents (Abiraterone, Docetaxel, Etoposide) in vitro. TAP1 treatment shortens the length of telomeres in ALDH⁺CD44⁺CXCR4⁺CD24⁺ cells and significantly reduces the expression of Homeobox B9 (HOXB9) and TGF-β2. In conclusion, PSA^-^/lo PCa cell-specific targeting peptide (TAP1) that suppressed PCa cell growth both in vitro and in vivo and improved the drug sensitivities of anti-androgens and chemotherapeutic agents at least through shortening the length of telomere and reducing the expression of HOXB9 and TGF-β2. Therapeutic peptides that specifically target prostate cancer stem cell might be a very valuable and promising approach to overcome chemoresistance and prevent recurrence in patients with PCa.

Keywords: Androgen deprivation therapy; Cancer stem cell; Peptide; Phage display; Prostate cancer.