Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

Dong, Jun; Wu, Zeyu; Wang, Dan; Pascal, Laura E.; Nelson, Joel B.; Wipf, Peter; Wang, Zhou

doi:10.1158/1535-7163.mct-18-0432

Cited by 28 publications

(27 citation statements)

References 68 publications

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“…Recent studies have also provided corroborating evidence that Hsp70 can bind to a region encompassing the AR tau 5 to enhance AR action (Dong et al 2019). Furthermore, small-molecule Hsp70 inhibitors, either alone or in synergy with enzalutamide, have been shown to inhibit the proliferation of 22Rv.1, a CRPC cell model (Dong et al 2019).…”

Section: Bag1l Regulation Of Ar Actionmentioning

confidence: 83%

“…Evidence that Hsp70 may be involved in BAG1L action at the AR N-terminus comes from surface plasmon resonance and functional studies that show that the BAG domain/AR tau 5 interaction is enhanced by the addition of Hsp70 (Shatkina et al 2003). Recent studies have also provided corroborating evidence that Hsp70 can bind to a region encompassing the AR tau 5 to enhance AR action (Dong et al 2019). Furthermore, small-molecule Hsp70 inhibitors, either alone or in synergy with enzalutamide, have been shown to inhibit the proliferation of 22Rv.1, a CRPC cell model (Dong et al 2019).…”

Section: Bag1l Regulation Of Ar Actionmentioning

confidence: 99%

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BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

Lee

Kuznik

Rottenberg

et al. 2019

Journal of Molecular Endocrinology

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Androgens are important determinants of normal and malignant prostate growth. They function by binding to the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR). All clinically approved AR-targeting antiandrogens for prostate cancer therapy function by competing with endogenous androgens. Despite initial robust responses to androgen deprivation therapy, nearly all patients with advanced prostate cancer relapse with lethal castration-resistant prostate cancer (CRPC). Progression to CRPC is associated with ongoing AR signaling, which in part, is due to the expression of constitutively active AR splice variants that contain the N-terminus of the receptor but lack the C-terminus. Currently, there are no approved therapies specifically targeting the AR N-terminus. Current pharmacologic targeting strategies for inhibiting the AR N-terminal region have proven difficult, due to its intrinsically unstructured nature and lack of enzymatic activity. An alternative approach is to target key molecules such as the cochaperone BAG1L that bind to and enhance the activity of the AR AF1. Here, we review recent literature that suggest Bag-1L is a promising target for AR-positive prostate cancer.

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Section: Bag1l Regulation Of Ar Actionmentioning

confidence: 83%

Section: Bag1l Regulation Of Ar Actionmentioning

confidence: 99%

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

Lee

Kuznik

Rottenberg

et al. 2019

Journal of Molecular Endocrinology

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“…HSPA1A is a multifunctional chaperone. Interestingly, in prostate cancer, HSPA1A interacts with the androgen receptor (AR) and regulates its activation [36]. HSPA1A is localized in both the cytosol and the membrane, and membrane-associated HSPA1A expression has been linked to cancer aggressiveness and resistance to cancer therapy [37,38].…”

Section: Discussionmentioning

confidence: 99%

The interactome of the prostate-specific protein Anoctamin 7

Kaikkonen

Takala

Pursiheimo

et al. 2020

CBM

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BACKGROUND: Elevated Anoctamin 7 (ANO7) expression is associated with poor survival in prostate cancer patients. OBJECTIVE: The aim was to discover proteins that interact with ANO7 to understand its functions and regulatory mechanisms. METHODS: The proximity-dependent biotin identification (BioID) method was utilized. ANO7 fused to biotin ligase was transiently transfected into LNCaP cells, and the biotinylated proteins were collected and analysed by mass spectrometry. Four identified proteins were stained with dual fluorescent immunostaining and visualized using Stimulated emission depletion microscopy (STED). RESULTS: After bioinformatic filtering steps, 64 potentially ANO7-interacting proteins were identified and analysed with the GO enrichment analysis tool. One of the most prominently enriched cellular components was cellular vesicle. Co-localization was showed for staphylococcal nuclease and tudor domain containing 1 (SND1), heat shock protein family A (Hsp70) member 1A (HSPA1A), adaptor related protein complex 2 subunit beta 1 (AP2B1) and coatomer protein complex subunit gamma 2 (COPG2). CONCLUSIONS: This is the first study in which ANO7 interacting proteins have been identified. Although further studies are needed, the findings reported here expand our understanding of the role and regulation of ANO7 in prostate cancer cells. Furthermore, these results are likely to introduce new targets for the novel cancer therapies.

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“…LNCaP and C4‐2 cells were stably transfected as described previously . Briefly, C4‐2 or LNCaP cells at 70‐80% confluency were transfected with 1 µg GFP‐AR WT or GFP‐AR F876L in six‐well plates using PolyJet In Vitro DNA Transfection Reagent (SignaGen) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

A novel androgen receptor antagonist JJ‐450 inhibits enzalutamide‐resistant mutant AR^F876L nuclear import and function

Wang

Yang

et al. 2019

The Prostate

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Background: Castration-resistant prostate cancer can develop resistance to enzalutamide because of androgen receptor (AR) point mutations, AR overexpression, constitutively active AR splice variants, and/or elevated intratumoral androgen synthesis. The point mutation AR F876L was reported to be stimulated, instead of inhibited, by enzalutamide, thus contributing to enzalutamide resistance. We have recently developed JJ-450 as a novel AR antagonist with the potential to treat enzalutamide-resistant castration-resistant prostate cancer (CRPC). Methods:We employed several assays to determine the impact of JJ-450 and enzalutamide on prostate cancer cell lines expressing green fluorescent protein (GFP)-AR F876L . These assays include a prostate-specific antigen enhancer/promoter-based luciferase assay to determine AR transcriptional activity, a quantitative real-time polymerase chain reaction assay, and Western blot analysis to detect expression of AR-target genes at the messenger RNA and protein level, fluorescence microscopy to show AR subcellular localization, and a 5-bromo-2′-deoxyuridine assay to measure prostate cancer cell proliferation.Results: As expected, enzalutamide inhibited wild-type (WT) AR but not AR F876L transcriptional activity in the luciferase assay. In contrast, JJ-450 inhibited both WT-AR and AR F876L transcriptional activity to a similar extent. Also, enzalutamide retarded androgen-induced nuclear import of GFP-AR, but not GFP-AR F876L , whereas JJ-450 retarded nuclear import of both GFP-AR and GFP-AR F876L . To further evaluate JJ-450 inhibition of AR F876L , we stably transfected C4-2 cells separately with GFP-AR or GFP-AR F876L . Enzalutamide inhibited endogenous AR-target gene expression in C4-2-GFP-AR WT , but not in the C4-2-GFP-AR F876L subline, whereas JJ-450 inhibited AR-target gene expression in both C4-2 sublines. More importantly, enzalutamide inhibited proliferation of C4-2-GFP-AR WT , but not of the C4-2-GFP-AR F876L subline, whereas JJ-450 inhibited proliferation of both C4-2 sublines.Conclusion: JJ-450 inhibits enzalutamide-resistant AR F876L mutant nuclear translocation and function. Our findings suggest that JJ-450 and its analogs should be further developed to provide a potential new approach for the treatment of enzalutamide-resistant CRPC.

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Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

Cited by 28 publications

References 68 publications

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

The interactome of the prostate-specific protein Anoctamin 7

A novel androgen receptor antagonist JJ‐450 inhibits enzalutamide‐resistant mutant AR^F876L nuclear import and function

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Hsp70 Binds to the Androgen Receptor N-terminal Domain and Modulates the Receptor Function in Prostate Cancer Cells

Cited by 28 publications

References 68 publications

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

The interactome of the prostate-specific protein Anoctamin 7

A novel androgen receptor antagonist JJ‐450 inhibits enzalutamide‐resistant mutant ARF876L nuclear import and function

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A novel androgen receptor antagonist JJ‐450 inhibits enzalutamide‐resistant mutant AR^F876L nuclear import and function