Suppressing BCL-XL increased the high dose androgens therapeutic effect to better induce the Enzalutamide-resistant prostate cancer autophagic cell death

Abstract

Most patients with advanced prostate cancer (PCa) initially respond well to androgen deprivation therapy (ADT) with antiandrogens, but most of them eventually become resistant to ADT. Here, we found that the antiandrogen Enzalutamide-resistant (EnzR) PCa cells can be suppressed by hyper-physiological doses of the androgen DHT. Mechanism dissection indicates that while androgens/androgen receptor (AR) can decrease BCL-2 expression to induce cell death, yet they can also simultaneously increase anti-apoptosis BCL-XL protein expression via decreasing its potential E3 ubiquitin ligase, PARK2, through transcriptionally increasing the miR-493-3p expression to target PARK2. Thus, targeting the high dose DHT/AR/miR-493-3p/PARK2/BCL-XL signaling with BCL-XL-shRNA can increase high-dose-DHT effect to better suppress EnzR cell growth via increasing the autophagic cell death. A preclinical study using in vivo mouse model also validated that suppressing BCL-XL led to enhance high dose DHT effect to induce PCa cell death. The success of human clinical trials in the future may help us to develop a novel therapy using high dose androgens to better suppress CRPC progression.

Role of ATP5G3 in sodium nitroprusside‐induced cell death in cervical carcinoma cells

“…Several studies have reported the involvement of Bcl-xL signaling in autophagic processes, [29,30] which corresponds to our findings in siATP5G3-transfected cells. We found complete inhibition of SNPinduced cytotoxicity by siBax.…”

“…[ 27,28 ] Such a finding implies a protective contribution of ATP5G3 to the inhibition of autophagic cell death induced by SNP. Several studies have reported the involvement of Bcl‐xL signaling in autophagic processes, [ 29,30 ] which corresponds to our findings in siATP5G3‐transfected cells. We found complete inhibition of SNP‐induced cytotoxicity by siBax.…”

“…Bcl-xL is localized in the mitochondria, cytosol, and endoplasmic reticulum (ER), and is also implicated in lysosomal localization. [29,30] Bax is present in the mitochondria, cytosol, ER, nucleus, and Golgi apparatus. Karch et al [31] clearly demonstrated the lysosomal localization of Bax and verified the Bax dependency of lysosomal membrane permeability in autophagic cell death using Baxdeficient cells.…”

Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer

“…A dose-dependent biphasic response of androgens has been reported for several genes ( 8 , 9 ). Similarly, androgens are also shown to have both growth-promoting and growth-repressive effects on PCa cells as well ( 27 , 28 ). In fact, high-dose androgen supplementation is being evaluated as a promising therapy for PCa in clinical trials ( 29 ).…”

Multi-candidate immunohistochemical markers to assess radiation response and prognosis in prostate cancer: results from the CHHiP trial of radiotherapy fractionation

“…Other proteins with anti-apoptotic functions, such as Mcl-1 and Bcl-xl, are known to contribute to therapy resistance in prostate cancer. 45 , 46 , 47 , 48 Robust evaluation of the apoptosis pathways to predict therapy outcome is likely to require assessment of multiple pro- and anti-apoptotic proteins in combination. 49 …”