Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression

Bery, Fanny; Figiel, Sandy; Kouba, Sana; Fontaine, Delphine; Guéguinou, Maxime; Potier-Cartereau, Marie; Vandier, Christophe; Guibon, Roseline; Bruyère, F.; Fromont, Gaëlle; Mahéo, Karine

doi:10.3390/ijms21134786

Cited by 26 publications

(20 citation statements)

References 27 publications

(49 reference statements)

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“…Indeed, we demonstrated that calcium signaling plays a major role in early EMT events. We identified a new positive feedback loop between Zeb1 and the calcium-activated potassium channel SK3, that promotes calcium entries and cellular migration [12,13]. This signaling pathway was highlighted in PCa cells and human PCa explants treated by EMT inducers (TGFβ and hypoxia).…”

Section: Introductionmentioning

confidence: 95%

“…We previously identified a positive feedback loop between Zeb1 and the SK3 potassium channel that contributes to prostate cancer cell migration [12,13]. The calcium-activated potassium channel SK3 is known to form complexes with Orai1 calcium channel to induce calcium entry that mediates an aggressive phenotype in human cancer cells [21].…”

Section: Enza Treatment Affect Sk3 and Orai Expression: Impact On Calcium Entry Pathwaysmentioning

confidence: 99%

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Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation

Bery

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Guéguinou

et al. 2021

Cancers

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Therapeutic strategies for metastatic castration-resistant prostate cancer aim to target androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease. Therapies targeting the androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the calcium signal can induce the transcription factor Zeb1, a key determinant of cell plasticity during tumor progression. The aim of this study was to determine whether the androgen receptor-targeted treatment Enzalutamide could induce dysregulation of the calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3 potassium channel are overexpressed in vivo in neuroendocrine castration-resistant prostate cancer and in vitro in LNCaP cells neurodifferentiated after Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly, Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by Enzalutamide. This study offers new perspectives to increase hormone therapy efficacy and improve clinical outcomes.

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Section: Introductionmentioning

confidence: 95%

Section: Enza Treatment Affect Sk3 and Orai Expression: Impact On Calcium Entry Pathwaysmentioning

confidence: 99%

Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation

Bery

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Guéguinou

et al. 2021

Cancers

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“…In PCa, independent observations in pre-clinical PCa models have linked tumor hypoxia to EMT (Bery et al, 2020;Tang et al, 2019), castration-resistance (Skov et al, 2004;Tran et al, 2020;Yapp et al, 2007), and acquisition of a small cell phenotype (Guo et al, 2019;Qi et al, 2010). In one study, formation of SCPCa in the TRAMP mouse model was suppressed in mice lacking the ubiquitin ligase Siah2, which regulates HIF-1a availability.…”

Section: Lineage Plasticity Triggers In the Tumor Microenvironment (Tme)mentioning

confidence: 99%

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

et al. 2020

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Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.

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“…Hypoxia regulates HIF signaling by promoting stabilization of HIF-1α, which can regulate target gene expression by binding to specific regulatory sequences in their promotor, the hypoxia response elements (HRE) ( 159 ). Hypoxia contributes to epithelial-mesenchymal transition (EMT) by binding to the HRE in TWIST ( 160 , 161 ) and ZEB1 ( 162 , 163 ), thereby supporting tumor invasiveness ( 164 ). Also, the downstream mechanisms of HIF-1α signaling influence cellular radioresistance by facilitating a metabolic switch, i.e.…”

Section: Radiotherapy and Metabolismmentioning

confidence: 99%

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

2021

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To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

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Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression

Cited by 26 publications

References 27 publications

Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation

Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio

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