Therapy escape mechanisms in the malignant prostate

Santer, Frédéric R.; Erb, Holger H.H.; McNeill, Rhiannon V.

doi:10.1016/j.semcancer.2015.08.005

Cited by 59 publications

(64 citation statements)

References 162 publications

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“…50 However, these studies differ in both detection methods and the cell culture conditions for the CSC population, which has been shown to be highly adaptive to the microenvironment. 51 The model used here was first introduced by Collins and colleagues in 1998, and the laboratory of Maitland and Collins has since then demonstrated the reliability of this model in several publications.…”

Section: Discussionmentioning

confidence: 99%

The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

et al. 2017

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Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF-κB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6-specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL-4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

et al. 2017

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“…Breast cancer is one of the most frequent tumors among women and still represents a major cause of mortality . Cancer cells are characterized by metabolic alterations, including depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect .…”

Section: Roles Of Foxo1 In Diverse Human Neoplasmsmentioning

confidence: 99%

Deciphering the roles of FOXO1 in human neoplasms

Jiang

Tian

Yang

et al. 2018

Intl Journal of Cancer

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Neoplasms constituted an enormous burden and contributed to an estimated 8.2 million deaths in 2012 worldwide. FOXO1 (forkhead box O1), a member of the forkhead box (FOX) family, is a transcriptional factor involved in diverse cellular functions. Herein, we concentrate on recent studies of the antineoplastic roles of FOXO1 in neoplasms. This article may serve as a guide for future research and identify FOXO1 as a potent therapeutic target in neoplasms.

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“…Antiapoptotic BCL‐2 proteins are frequently overexpressed in cancer and are associated with an aggressive, treatment‐refractory disease. In prostate cancer, several studies demonstrate that overexpression of antiapoptotic BCL2 proteins are adverse prognostic factors associated with disease progression and therapy resistance . Increased expression of these antiapoptotic proteins can suppress apoptosis by sequestering the proapoptosis players and preventing activation BAX and BAK.…”

Section: Introductionmentioning

confidence: 99%

Targeting prosurvival BCL2 signaling through Akt blockade sensitizes castration‐resistant prostate cancer cells to enzalutamide

Pilling

Hwang

2019

The Prostate

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Background Prostate cancer that recurs after initial treatment inevitably progresses to castration‐resistant prostate cancer (CRPC), the lethal stage of the disease. Despite improvements in outcomes from next generation androgen receptor (AR)‐axis inhibitors, CRPC remains incurable. Therapeutic strategies to target AR antagonist resistance are urgently needed to improve outcomes for men with this lethal form of prostate cancer. Methods Apoptosis and BCL2 family signaling were characterized in cell line models of CRPC. Quantitative real‐time polymerase chain reaction and Western blot analysis were used to determine BCL2 expression levels. Drug sensitivity was determined by proliferation, survival and apoptosis analysis. Protein‐protein interactions were evaluated by coimmunoprecipitation followed by Western blot detection. Results In the present study, we identify antiapoptotic BCL2 protein signaling as a mechanism of resistance to AR antagonist enzalutamide. In CRPC cell line models, we found that BCL‐xL and MCL‐1 proteins block apoptosis through binding and sequestering proapoptotic proteins BIM and BAX, resulting in cell survival in response to enzalutamide. Treatment with BH3‐mimetics targeting BCL‐xL or MCL‐1 disrupts these interactions and activates apoptosis, sensitizing CRPC cells to enzalutamide. Importantly, we demonstrate that PI3K/Akt signaling is activated in response to enzalutamide and mediates apoptosis evasion through inactivation of BAD, a BH3‐only protein that activates proapoptotic signlaing through inhbition of BCL‐xL. Inhibition of Akt activates BAD, resulting in increased apoptosis and sensitivity to enzalutamide, demonstrating an alternative therapeutic strategy to target drug resistance. Conclusions These results demonstrate that CRPC cells employ multiple mechanisms to mediate apoptosis evasion through BCL2 signaling, suggesting this pathway is critical for survival. This study provides a strong preclinical rationale for developing therapeutic strategies to target antiapoptotic BCL2 signaling in combination with AR antagonists to improve treatment options for patients with advanced prostate cancer.

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Therapy escape mechanisms in the malignant prostate

Cited by 59 publications

References 162 publications

The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

Deciphering the roles of FOXO1 in human neoplasms

Targeting prosurvival BCL2 signaling through Akt blockade sensitizes castration‐resistant prostate cancer cells to enzalutamide

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