Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(20), P. 11088 - 11088

Published: Oct. 14, 2021

Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted are the gold standard options for treating prostate cancer (PCa). These initially effective, as localized early stage of metastatic disease androgen- castration-sensitive. The tumor strongly relies on systemic/circulating androgens activating AR signaling to stimulate growth progression. However, after a certain point, will eventually develop resistant stage, where ADT antagonists no longer effective. Mechanistically, it seems that becomes more aggressive through adaptive responses, alternative activated pathways, is less dependent signaling. This includes hyperactivation PI3K-AKT-mTOR pathway, which central signal regulates cell pro-survival/anti-apoptotic thus, compensating blockade pathway well-documented its crosstalk between genomic non-genomic signaling, well other cascades. Such reciprocal feedback loop makes complicated target individual factor/signaling PCa. Here, we highlight role resistance mechanism PCa illustrate transition from signaling-dependent pathway-dependent. Moreover, therapeutic strategies with inhibitors targeting used in clinic ongoing clinical trials discussed.

Language: Английский

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Molecular Landscape of LncRNAs in Prostate Cancer: A focus on pathways and therapeutic targets for intervention

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: July 1, 2022

Abstract Background One of the most malignant tumors in men is prostate cancer that still incurable due to its heterogenous and progressive natures. Genetic epigenetic changes play significant roles development. The RNA molecules with more than 200 nucleotides length are known as lncRNAs these factors do not encode protein. They regulate gene expression at transcriptional, post-transcriptional levels. LncRNAs vital biological functions cells pathological events, hence their undergoes dysregulation. Aim review role alterations development emphasized here. Therefore, were chosen for this purpose level interaction other signaling networks progression examined. Key scientific concepts aberrant has been well-documented rate tumor regulated via affecting STAT3, NF-κB, Wnt, PI3K/Akt PTEN, among molecular pathways. Furthermore, radio-resistance chemo-resistance features cells. Overexpression tumor-promoting such HOXD-AS1 CCAT1 can result drug resistance. Besides, induce immune evasion upregulating PD-1. Pharmacological compounds quercetin curcumin have applied targeting lncRNAs. siRNA tool reduce thereby suppressing progression. Prognosis diagnosis clinical course be evaluated by exosomal lncRNA-p21 investigated serum patients a reliable biomarker.

Language: Английский

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Current therapy and drug resistance in metastatic castration-resistant prostate cancer

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 68, P. 100962 - 100962

Published: April 14, 2023

Castration-resistant prostate cancer (CRPC), especially metastatic castration-resistant (mCRPC) is one of the most prevalent malignancies and main cause cancer-related death among men in world. In addition, it very difficult for clinical treatment because natural or acquired drug resistance CRPC. Mechanisms are extremely complicated how to overcome remains an urgent problem be solved. Thus, a comprehensive thorough understanding mechanisms mCRPC indispensable develop novel better therapeutic strategies. this review, we aim review new insight elucidate governing drugs: taxanes, androgen receptor signaling inhibitors (ARSIs) poly (ADP-ribose) polymerase (PARP) (PARPi). Most importantly, order improve efficacy these drugs, strategies overcoming also discussed based on their respectively.

Language: Английский

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Nano Proteolysis Targeting Chimeras (PROTACs) with Anti‐Hook Effect for Tumor Therapy

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(37)

Published: July 24, 2023

Abstract Proteolysis targeting chimera (PROTAC) is an emerging pharmacological modality with innovated post‐translational protein degradation capabilities. However, off‐target induced unintended tissue effects and intrinsic “hook effect” hinder PROTAC biotechnology to be maturely developed. Herein, intracellular fabricated nano proteolysis chimeras (Nano‐PROTACs) a center‐spoke network for achieving efficient dose‐dependent in tumor reported. The precursors are triggered by higher GSH concentrations inside cells, which subsequently situ self‐assemble into Nano‐PROTACs through intermolecular hydrogen bond interactions. fibrous can form effective polynary complexes E3 ligases multi‐binding sites, “anti‐hook effect”. generality efficacy of validated degrading variable interest (POI) such as epidermal growth factor receptor (EGFR) androgen (AR) wide‐range manner 95 % rate long‐lasting potency up 72 h vitro. Significantly, achieve vivo 79 inhibition A549 LNCap xenograft mice models, respectively. Taking advantages self‐assembly strategy, the provide generalizable platform promote precise clinical translational application PROTAC.

Language: Английский

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Calcium signalling pathways in prostate cancer initiation and progression

Nature Reviews Urology, Journal Year: 2023, Volume and Issue: 20(9), P. 524 - 543

Published: March 24, 2023

Language: Английский

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WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth

Cancer Research, Journal Year: 2023, Volume and Issue: 83(7), P. 1016 - 1030

Published: Jan. 6, 2023

Noncanonical Wnt signaling by WNT5a has oncogenic and tumor suppressive activities, but downstream pathways mediating these specific effects remain to be fully established. In a subset of prostate cancer organoid culture xenograft models, inhibition synthesis stimulated growth, whereas or mimetic peptide (Foxy5) markedly suppressed growth. caused ROR2-dependent decrease in YAP1 activity, which was associated with increased phosphorylation MST1/2, LATS1, MOB1, YAP1, indicating Hippo pathway activation. Deletion MST1/2 abrogated the response. similarly activated ROR2-expressing melanoma cells, ROR2-negative cells Hippo. This suppression inhibitory NF2/Merlin that not observed cells. also mRNA encoding components including MST1 MST2 positively correlated clinical datasets. Conversely, ROR2 expression activity datasets, revealing WNT5a/ROR2 negative feedback loop modulate activity. Together findings identify activation as mechanism mediates indicate may predictive biomarker for responsiveness WNT5a-mimetic drugs.WNT5a through activates downregulate YAP1/TAZ suppress identifying potential patients could benefit from WNT5a-related agents.

Language: Английский

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Molecular panorama of therapy resistance in prostate cancer: a pre-clinical and bioinformatics analysis for clinical translation

Cancer and Metastasis Reviews, Journal Year: 2024, Volume and Issue: 43(1), P. 229 - 260

Published: Feb. 19, 2024

Language: Английский

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Hormonal regulation of telomerase activity and hTERT expression in steroid-regulated tissues and cancer

Cancer Cell International, Journal Year: 2022, Volume and Issue: 22(1)

Published: Aug. 16, 2022

Abstract Naturally, in somatic cells chromosome ends (telomeres) shorten during each cell division. This process ensures to limit proliferation of avoid malignant proliferation; however, it leads proliferative senescence. Telomerase contains the reverse transcriptase TERT, which together with TERC component, is responsible for protection genome integrity by preventing shortening telomeres through adding repetitive sequences. In addition, telomerase has non-telomeric function and supports growth factor independent growth. Unlike cells, detectable stem germ line cancer support self-renewal expansion. Elevated activity reported almost all human cancers. Increased expression hTERT gene or its reactivation required limitless cellular immortal cells. hormonally regulated tissues as well prostate, breast endometrial cancers, are under control steroid sex hormones factors. Also, a number factors known play role carcinogenesis via regulation levels activity. Understanding interaction may help finding therapeutical targets anticancer strategies. this review, we outline roles functions several regulation, particularly hormone cancers such cancer.

Language: Английский

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The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

Cancers, Journal Year: 2022, Volume and Issue: 14(12), P. 2887 - 2887

Published: June 11, 2022

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed among men worldwide 2020, first North America Europe. Patients with localized disease usually respond well to first-line treatments, however, up 30% develop castration-resistant (CRPC), which is often metastatic, making this stage of incurable ultimately fatal. Over last years, interest has grown into extracellular matrix (ECM) stiffening as an important mediator diseases, including cancers. While process increasingly well-characterized breast cancer, a similar in-depth look at ECM lacking for cancer. In review, we scrutinize current state literature regarding its potential association progression castration resistance.

Language: Английский

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Distinct mechanisms mediating therapy-induced cellular senescence in prostate cancer

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: Dec. 15, 2022

Abstract Background Prostate cancer (PCa) is an age-related malignancy in men with a high incidence rate. PCa treatments face many obstacles due to cell resistance and bypassing mechanisms escape therapy. According the intricacy of PCa, standard therapies are being used depending on stages including radical prostatectomy, radiation therapy, androgen receptor (AR) targeted therapy (androgen deprivation supraphysiological androgen, AR antagonists) chemotherapy. Most aforementioned have been implicated induce cellular senescence. Cellular senescence defined as stable cycle arrest G1 phase one that prevent proliferation. Results In this review, we provide analyze different therapy-induced (TIS) their effects tumor. Interestingly, it seems molecular pathways by cells for TIS. Understanding complexity underlying very critical its role tumorigenesis. The most prevalent analyzed TIS p53/p21 WAF1/CIP1 , p15 INK4B /p16 INK4A /pRb/E2F/Cyclin D, ROS/ERK, p27 Kip1 /CDK/pRb, /Skp2/C/EBP β signaling. Despite growth inhibition, senescent highly metabolically active. addition, secretome, which termed senescence-associated secretory phenotype (SASP), affects within tumor microenvironment neighboring non-tumor thereby may regulate tumors. Induction therefore double-edged sword can lead reduced or enhanced growth. Conclusion Thus, dependent type inducer specific senescence-induced pathway, useful develop pathway-specific senolytic compounds specifically targeting order evict reduce SASP side effects.

Language: Английский

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