Androgens modify therapeutic response to cabazitaxel in models of advanced prostate cancer.
Androgen Antagonists
/ pharmacology
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Dihydrotestosterone
/ pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Humans
Immunohistochemistry
Male
Mice
Mice, Nude
Orchiectomy
Prostatic Neoplasms
/ drug therapy
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Random Allocation
Receptors, Androgen
/ metabolism
Taxoids
/ pharmacology
Xenograft Model Antitumor Assays
kinesins
prostate tumors
taxane chemotherapy
therapeutic resistance
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
16
12
2019
accepted:
01
05
2020
pubmed:
17
6
2020
medline:
29
9
2020
entrez:
17
6
2020
Statut:
ppublish
Résumé
Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer. To examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days. Cell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner. Our findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.
Sections du résumé
BACKGROUND
Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer.
METHODS
To examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days.
RESULTS
Cell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner.
CONCLUSIONS
Our findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.
Identifiants
pubmed: 32542812
doi: 10.1002/pros.24015
pmc: PMC7880610
mid: NIHMS1662512
doi:
Substances chimiques
AR protein, human
0
Androgen Antagonists
0
Antineoplastic Agents
0
Receptors, Androgen
0
Taxoids
0
Dihydrotestosterone
08J2K08A3Y
cabazitaxel
51F690397J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
926-937Subventions
Organisme : NCI NIH HHS
ID : P30 CA177558
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA232574
Pays : United States
Organisme : NCI NIH HHS
ID : CA232574
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals LLC.
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