scholarly journals Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4854
Author(s):  
Celina Ebersbach ◽  
Alicia-Marie K. Beier ◽  
Christian Thomas ◽  
Holger H. H. Erb
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Therapy Resistance ◽  
High Grade ◽  
Biological Processes ◽  
Signal Transducers ◽  
Stat Proteins ◽  
Docetaxel Resistance ◽  
Tumor Progress ◽  
Resistance Expression

Signal transducers and activators of transcription (STATs) are a family of transcription factors involved in several biological processes such as immune response, cell survival, and cell growth. However, they have also been implicated in the development and progression of several cancers, including prostate cancer (PCa). Although the members of the STAT protein family are structurally similar, they convey different functions in PCa. STAT1, STAT3, and STAT5 are associated with therapy resistance. STAT1 and STAT3 are involved in docetaxel resistance, while STAT3 and STAT5 are involved in antiandrogen resistance. Expression of STAT3 and STAT5 is increased in PCa metastases, and together with STAT6, they play a crucial role in PCa metastasis. Further, expression of STAT3, STAT5, and STAT6 was elevated in advanced and high-grade PCa. STAT2 and STAT4 are currently less researched in PCa. Since STATs are widely involved in PCa, they serve as potential therapeutic targets. Several inhibitors interfering with STATs signaling have been tested unsuccessfully in PCa clinical trials. This review focuses on the respective roles of the STAT family members in PCa, especially in metastatic disease and provides an overview of STAT-inhibitors evaluated in clinical trials.

A gene expression signature to predict high-grade prostate cancer response to oxaliplatin.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 150-150
Author(s):  
Philippe Pourquier ◽  
Stephane Puyo ◽  
Pierre Richaud ◽  
Jacques Robert ◽  
Nadine Houede
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Trials ◽  
Cell Lines ◽  
Gene Expression Signature ◽  
Chemotherapeutic Agents ◽  
Low Grade ◽  
Gleason Grade ◽  
High Grade ◽  
Expression Signature

150 Background: Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade prostate cancers are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low. Moreover, none of these trials took into account the tumor grade. Methods: We used an in silico approach to screen for drug candidates that could be used as an alternative to taxanes, based on a 86 genes signature which could distinguish between low-grade and high-grade tumors. We extracted from the NCI60 panel databases the expression profiles of the 86 genes across 60 human tumor cell lines and the corresponding in vitro cytotoxicity data of 152 drugs and looked for correlation between their expression level and cell sensitivity to each of these drugs. Results: Among the 86 genes, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the 60 cell lines was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. This signature was validated at the functional level since repression of each of these genes conferred a significant change in the sensitivity of PCa cell lines to oxaliplatin but not cisplatin. Conclusions: Our results provide a proof of concept that gene expression signature specific from high grade PCa could be used for the identification of alternative therapies to taxanes. They could also be used to select patients for further clinical trials and as predictive markers of response to these drugs, which represents a further step forward towards personalized therapy of PCa.

scholarly journals ADRB2-Targeting Therapies for Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 358 ◽  
Author(s):  
George Kulik
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Signaling Pathways ◽  
Therapy Resistance ◽  
Pathway Activation ◽  
Dependent Protein ◽  
Β Blocker ◽  
Survival Signaling ◽  
Pka Pathway ◽  
Propranolol Therapy

There is accumulating evidence that β-2 adrenergic receptor (ADRB2) signaling contributes to the progression and therapy resistance of prostate cancer, whereas availability of clinically tested β-blocker propranolol makes this pathway especially attractive as potential therapeutic target. Yet even in tumors with active ADRB2 signaling propranolol may be ineffective. Inhibition of apoptosis is one of the major mechanisms by which activation of ADRB2 contributes to prostate cancer pathophysiology. The signaling network that controls apoptosis in prostate tumors is highly redundant, with several signaling pathways targeting a few critical apoptosis regulatory molecules. Therefore, a comprehensive analysis of ADRB2 signaling in the context of other signaling mechanisms is necessary to identify patients who will benefit from propranolol therapy. This review discusses how information on the antiapoptotic mechanisms activated by ADRB2 can guide clinical trials of ADRB2 antagonist propranolol as potential life-extending therapy for prostate cancer. To select patients for clinical trials of propranolol three classes of biomarkers are proposed. First, biomarkers of ADRB2/cAMP-dependent protein kinase (PKA) pathway activation; second, biomarkers that inform about activation of other signaling pathways unrelated to ADRB2; third, apoptosis regulatory molecules controlled by ADRB2 signaling and other survival signaling pathways.

scholarly journals Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Qing Shi ◽  
Yasheng Zhu ◽  
Jian Ma ◽  
Kun Chang ◽  
Dongling Ding ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hybrid Methods ◽  
Biological Significance ◽  
Therapy Resistance ◽  
Dependent Manner ◽  
Gene Encoding ◽  
Docetaxel Resistance ◽  
Cancer Pathogenesis

Abstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance. Methods We identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer. Results The cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1-dependent manner. Knockout of SPOP or expression of prostate cancer-associated SPOP mutants conferred resistance to death caused by SG inducers (e.g. docetaxel, sodium arsenite and H2O2) in prostate cancer cells. Conclusions SG assembly is aberrantly elevated in SPOP-mutated prostate cancer. SPOP mutations cause resistance to cellular stress induced by chemtherapeutic drug such as docetaxel in prostate cancer.

PD-L1 Inhibitors for the Treatment of Prostate Cancer

2020 ◽  
Vol 21 (15) ◽  
pp. 1558-1565
Author(s):  
Matteo Santoni ◽  
Francesco Massari ◽  
Liang Cheng ◽  
Alessia Cimadamore ◽  
Marina Scarpelli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
T Lymphocytes ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Response To Therapy ◽  
Complex Series

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

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