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Therapeutic targets and signaling pathways of active components of QiLing decoction against castration-resistant prostate cancer based on network pharmacology.

ABSTRACT: QiLing decoction (QLD) is a traditional Chinese medicine compound. This study aims to explore the therapeutic effect of QLD in castration-resistant prostate cancer (CRPC) and its potential bio-targets. A total of 51 active components and QLD 149 targets were identified using bioinformatics analysis. Additionally, five optimal hub target genes were screened including tumor protein P53 (TP53), interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), caspase-3 (CASP-3), and estrogen receptor-1 (ESR-1). The interrelated network between active components of QLD and their potential targets was constructed. The molecular function, biological processes, and signaling pathways of QLD-against CRPC were identified. Moreover, QLD was found to efficiently exert a repressive effect on CRPC tumor growth mainly by suppressing the activation of HIF-α/VEGFA and TNF-α/IL6 signaling pathways, and increasing the P53 expression level. These results successfully indicated the potential anti-CRPC mechanism of the active components of QLD.

SUBMITTER: Cao H

PROVIDER: S-EPMC9245566 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Therapeutic targets and signaling pathways of active components of QiLing decoction against castration-resistant prostate cancer based on network pharmacology.

Cao Hongwen H Wang Dan D Gao Renjie R Li Chenggong C Feng Yigeng Y Chen Lei L

PeerJ 20220627

QiLing decoction (QLD) is a traditional Chinese medicine compound. This study aims to explore the therapeutic effect of QLD in castration-resistant prostate cancer (CRPC) and its potential bio-targets. A total of 51 active components and QLD 149 targets were identified using bioinformatics analysis. Additionally, five optimal hub target genes were screened including tumor protein P53 (TP53), interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), caspase-3 (CASP-3), and estrogen rec ...[more]

PMID: 35782093

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Project description:The success of the PROfound, IPATential150, and TheraP trials promoted the transition from sequential treatment to therapeutic targets (TTs)-guided precision treatment in metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the prevalence and prognostic value of TTs from these three trials. All included Chinese mCRPC patients underwent circulating tumor DNA (ctDNA) sequencing, PTEN status assessment, and dual-tracer [68 Ga-prostate-specific membrane antigen (PSMA) and 18 F-fluorodexyglucose (FDG)] positron emission tomography/computed tomography (PET/CT). Previous treatment with cabazitaxel, Lu-PSMA or olaparib was unallowed. Patients with known significant sarcomatoid or spindle cell or neuroendocrine small cell components were also excluded. TTs were defined as positive as follows: (a) high PSMA and no PSMA-/FDG+ disease on dual-tracer PET/CT scans; (b) defects in homologous recombination repair (HRR) genes in ctDNA; and (c) loss of PTEN immunohistochemistry staining in tumor tissue. The prevalence and prognostic value on progression-free survival (PFS) of TTs were evaluated. A total of 106 consecutive mCRPC patients were included. The prevalence of positive PET/CT, HRR defect, and PTEN loss was 30%, 29% and 16%, respectively. Sixty-three patients had at least one TT. Metastatic volume (odds ratio = 5.0; P = 0.017) was the only independent factor of positive TT in multivariate analysis. Seventy-four patients received abiraterone after TT screening. Patients with positive PET/CT (P = 0.011) and HRR defect (P = 0.002) had a significantly shorter PFS after receiving abiraterone than patients with negative TTs. However, PTEN status was unrelated to PFS, which may be due to a less number of patients with PTEN loss (P = 0.952). Overall, patients with any positive TTs had a significantly shorter PFS after abiraterone than patients with negative TTs (P = 0.009). Nearly 60% of Chinese patients with mCRPC who had a poor prognosis on abiraterone were candidates for precision treatments based on the specific criteria of TTs.

Project description:Untreated prostate cancers rely on androgen receptor (AR) signaling for growth and survival, forming the basis for the initial efficacy of androgen deprivation therapy (ADT). Yet, the disease can relapse and progress to a lethal stage termed castration-resistant prostate cancer (CRPC). Reactivation of AR signaling represents the most common driver of CRPC growth and next generation AR signaling inhibitors (ARSIs) are now used in combination with ADT as a first line therapy. However, ARSIs can result in selective pressure generating AR-independent tumors. The transition from AR-dependence frequently accompanies a change in phenotype resembling developmental trans-differentiation or Ã¢Â€Â˜lineage plasticityÃ¢Â€Â™. Neuroendocrine prostate cancer, which lacks a defined pathologic classification, is the most studied type of lineage plasticity. However, most AR-null tumors do not exhibit neuroendocrine features and are classified as Ã¢Â€Â˜double-negative prostate cancerÃ¢Â€Â™, the drivers of which are poorly defined. Lineage plasticity studies in CRPC are limited by the lack of genetically defined patient-derived models that recapitulate the disease spectrum. To address this, we developed a biobank of organoids generated from patient biopsies to study the landscape of metastatic CRPC and allow for functional validation assays. Proteins called transcription factors (TFs) are drivers of tumor lineage plasticity. To identify the key TFs that drive the growth of AR-independent tumors, we integrated epigenetic and transcriptomic data generated from CRPC models. By presenting a map of the chromatin accessibility and transcriptomic landscape of CRPC using a diverse biobank of organoids, PDXs and cell lines that recapitulate the heterogeneity of metastatic prostate cancer, we validate CRPC-AR and CRPC-NE subtypes and reveal two subtypes of AR-negative/low samples as well as their respective masterTFs. Additional analysis revealed a model in which YAP, TAZ, TEAD and AP-1 function together and drive oncogenic growth in CRPC-SCL samples. Overall, we show here how an approach to stratify CRPC patients into four subtypes using their transcriptomic signatures can potentially inform upon appropriate clinical decisions.

Dataset Information

Therapeutic targets and signaling pathways of active components of QiLing decoction against castration-resistant prostate cancer based on network pharmacology.

Publications

Therapeutic targets and signaling pathways of active components of QiLing decoction against castration-resistant prostate cancer based on network pharmacology.

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