Docetaxel radiosensitizes castration-resistant prostate cancer by downregulating CAV-1: International Journal of Radiation Biology: Vol 0, No 0

Docetaxel radiosensitizes castration-resistant prostate cancer by downregulating CAV-1: International Journal of Radiation Biology: Vol 0, No 0

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Docetaxel radiosensitizes castration-resistant prostate cancer by downregulating CAV-1

Nrusingh C. Biswal
6–7 minutes

Abstract

Purpose:

Docetaxel (DXL), a noted radiosensitizer, is one of the few chemotherapy drugs approved for castration-resistant prostate cancer (CRPC), though only a fraction of CRPCs respond to it. CAV-1, a critical regulator of radioresistance, has been known to modulate DXL and radiation effects. Combining DXL with radiotherapy may create a synergistic anticancer effect through CAV-1 and improve CRPC patients’ response to therapy. Here, we investigate the effectiveness and molecular characteristics of DXL and radiation combination therapy in vitro.

Materials and methods:

We used live/dead assays to determine the IC50 of DXL for PC3, DU-145, and TRAMP-C1 cells. Colony formation assay was used to determine the radioresponse of the same cells treated with radiation with/without IC50 DXL (4, 8, and 12 Gy). We performed gene expression analysis on public transcriptomic data collected from human-derived prostate cancer cell lines (C4-2, PC3, DU-145, and LNCaP) treated with DXL for 8, 16, and 72 hours. Cell cycle arrest and protein expression were assessed using flow cytometry and western blot, respectively.

Results:

Compared to radiation alone, combination therapy with DXL significantly increased CRPC death in PC3 (1.48-fold, p < .0001), DU-145 (1.64-fold, p < .05), and TRAMP-C1 (1.13-fold, p < .05) at 4 Gy of radiation. Gene expression of CRPC treated with DXL revealed downregulated genes related to cell cycle regulation and upregulated genes related to immune activation and oxidative stress. Confirming the results, G2/M cell cycle arrest was significantly increased after treatment with DXL and radiation. CAV-1 protein expression was decreased after DXL treatment in a dose-dependent manner; furthermore, CAV-1 copy number was strongly associated with poor response to therapy in CRPC patients.

Conclusions:

Our results suggest that DXL sensitizes CRPC cells to radiation by downregulating CAV-1. DXL + radiation combination therapy may be effective at treating CRPC, especially subtypes associated with high CAV-1 expression, and should be studied further.

Author contributions

K.J.T.: data collection, formal analysis, bioinformatic analyses, methodology, and writing - original draft, review and editing. S.K.R.: data collection, formal analysis, and writing - review and editing. Z.K.: data collection, writing - review and editing. M.R.G.: conceptualization, review and editing. H.D.S.: conceptualization, methodology, project administration, funding acquisition, visualization, and writing - review and editing. N.C.B.: conceptualization, methodology, project administration, funding acquisition, visualization, review and editing.

Disclosure statement

The authors report there are no competing interests to declare.

Data availability statement

Microarray data can be accessed in NCBI GEO (GSE63479 and GSE83654). Data can also be provided by the corresponding author upon reasonable request.

Additional information

Funding

H.D.S. and N.C.B. were supported by a seed grant from the University of Maryland School of Medicine, Department of Radiation Oncology. K.J.T. was supported by a Banneker/Key Scholarship provided by the University of Maryland Honors College.

Notes on contributors

Kevin J. Tu

Kevin J. Tu is a graduate student at the University of Cambridge, Cancer Research UK Cambridge Institute, and medical student at the University of Maryland School of Medicine.

Sanjit K. Roy

Sanjit K. Roy is a postdoctoral fellow at the University of Maryland School of Medicine Department of Radiation Oncology.

Zachery Keepers

Zachery Keepers is a medical student at the University of Maryland School of Medicine.

Manas R. Gartia

Manas R. Gartia received his PhD in Nuclear, Plasma and Radiological Engineering at the University of Illinois at Urbana-Champaign. He is currently an associate professor in the Department of Mechanical & Industrial Engineering at Louisiana State University.

Hem D. Shukla

Hem D. Shukla received his PhD in Biochemistry at R. D. University Jabalpur in India and completed his postdoctoral training from University of Massachusetts. He is currently an assistant professor in the Department of Radiation Oncology at the University of Maryland School of Medicine.

Nrusingh C. Biswal

Nrusingh C. Biswal received his Ph.D. in Electrical and Biomedical Engineering at University of Connecticut, Storrs, CT under the supervision of Dr. Quing Zhu. He is currently an assistant professor in the Department of Radiation Oncology at the University of Maryland School of Medicine.

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