Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration-Resistant Prostate Cancer

Abstract

Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. , Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy. These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. .

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

“…While beyond the scope of this particular study, a better understanding of these differences could potentially lead to more effective inhibition of viral replication. At present, we chose JG40 and JG345 for the further studies because of JG40’s relatively broad spectrum and JG345’s favorable pharmacokinetic properties (Moses et al, 2018; Shao et al, 2018). …”

“…JG345 was admin-istered daily at 3 mg/kg starting a day before the infection and compared to vehicle (Figure 6C). This dosing scheme was based on previously reported mouse pharmacokinetics and pharmaco- dynamics (Moses et al, 2018; Shao et al, 2018). Consistent with these previous studies, JG345 had minimal effect on body weight (<5% reduction) in treated animals (Figure S6D).…”

Dysregulation of splicing-related proteins in prostate cancer is controlled by FOXA1

“…We also identify the SRP 250 HSPA8, which encodes a heat shock protein (HSP) scaffold in the core spliceosome complex 52 , as 251 a FOXA1-regulated gene that exhibited a high dependency for PCa cells. Therapeutic targeting the 252 HSP family member HSP90 has been shown to harbour anti-tumour activity and also modulate AS in 253 CRPCa 53,54 . 254…”

Managing the Spatial Covariance of Genetic Diversity in Niemann-Pick C1 Through Modulation of the Hsp70 Chaperone System

“…Understanding how genetic diversity contributes to health and disease in the human population is a problem that continues to confounds medical practice [1,2]. This challenge has led to the need for a high definition [3] or precision medicine approach (https://allofus.nih.gov/) to address the more than ~10,000 familial and somatic rare diseases [4,] as well as the somatic diseases leading to cancer [5,6] and the accumulation of variants over a lifespan that lead to numerous neurodegenerative disorders [7,8].…”

“…Protein folding is actively managed, in part, by heat shock cognate (Hsc) and inducible heat shock protein (Hsp) 70 chaperone/co-cochaperone system (referred to collectively as Hsp70) that comprises nearly 5% of cytoplasmic protein pool [16]. The Hsp70 system comprises a network of proteins mediating nascent protein synthesis, folding, stability, degradation, and mediates aggregation [6,7,[29][30][31]. Hsp70 is assisted by Hsp40 co-chaperones that stimulate the ATPase activity of Hsp70 [32][33][34][35][36] and nuclear exchange factors (NEFs), such as the BCL-anthogene (BAG) family members, which promote ADP and client protein release [7,[37][38][39]].…”