Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

Tiwari, R. S.; Manzar, Nishat; Bhatia, Vipul; Yadav, Anjali; Nengroo, Mushtaq Ahmad; Datta, Dipak; Carskadon, Shannon; Gupta, Nilesh; Sigouros, Michael; Khani, Francesca; Poutanen, Matti; Zoubeidi, Amina; Beltran, Himisha; Palanisamy, Nallasivam; Ateeq, Bushra

doi:10.1038/s41467-019-14184-0

Cited by 67 publications

(71 citation statements)

References 72 publications

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“…Additionally, a subset of NEPC patients exhibit elevated levels of SPINK1, suggesting its role in the maintenance of the NE-like phenotype (Tiwari et al, 2020).…”

Section: Cell-intrinsic Factorsmentioning

confidence: 99%

Dynamics of Cellular Plasticity in Prostate Cancer Progression

Tiwari

Manzar

Ateeq

2020

Front. Mol. Biosci.

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Despite the current advances in the treatment for prostate cancer, the patients often develop resistance to the conventional therapeutic interventions. Therapy-induced drug resistance and tumor progression have been associated with cellular plasticity acquired due to reprogramming at the molecular and phenotypic levels. The plasticity of the tumor cells is mainly governed by two factors: cell-intrinsic and cell-extrinsic. The cell-intrinsic factors involve alteration in the genetic or epigenetic regulators, while cell-extrinsic factors include microenvironmental cues and drug-induced selective pressure. Epithelial-mesenchymal transition (EMT) and stemness are two important hallmarks that dictate cellular plasticity in multiple cancer types including prostate. Emerging evidence has also pinpointed the role of tumor cell plasticity in driving anti-androgen induced neuroendocrine prostate cancer (NEPC), a lethal and therapy-resistant subtype. In this review, we discuss the role of cellular plasticity manifested due to genetic, epigenetic alterations and cues from the tumor microenvironment, and their role in driving therapy resistant prostate cancer.

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“…Additionally, a subset of NEPC patients exhibit elevated levels of SPINK1, suggesting its role in the maintenance of the NE-like phenotype (Tiwari et al, 2020).…”

Section: Cell-intrinsic Factorsmentioning

confidence: 99%

Dynamics of Cellular Plasticity in Prostate Cancer Progression

Tiwari

Manzar

Ateeq

2020

Front. Mol. Biosci.

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“…Among the predicted pathways, SPINK1-metallothionein signaling was the top pathway with a significant correlation ( Figure 2C,D). The aberrant activation of SPINK1 signaling could contribute to tumor malignancy, including increased invasion and proliferation of tumor cells [13][14][15]. Both SPINK1 and the metallothionein gene family, including MT1F, MT1G, MT1H, and MT3, were downregulated in the comparison of DDX3X high versus DDX3X low (Figure 2E), suggesting DDX3X's critical role in repressing RCC progression.…”

Section: Knowledge-based Transcriptomic Analysis Revealed That the Spmentioning

confidence: 99%

DDX3X is Epigenetically Repressed in Renal Cell Carcinoma and Serves as a Prognostic Indicator and Therapeutic Target in Cancer Progression

Lin

2020

IJMS

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DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked (DDX3X) is a member of the DEAD-box family of RNA helicases whose function has been revealed to be involved in RNA metabolism. Recent studies further indicate the abnormal expression in pan-cancers and the relevant biological effects on modulating cancer progression. However, DDX3X’s role in renal cell carcinoma (RCC) progression remains largely unknown. In this study, a medical informatics-based analysis using The Cancer Genome Atlas (TCGA) dataset was performed to evaluate clinical prognoses related to DDX3X. The results suggest that DDX3X is epigenetically repressed in tumor tissue and that lower DDX3X is correlated with the poor overall survival of RCC patients and high tumor size, lymph node metastasis, and distant metastasis (TNM staging system). Furthermore, knowledge-based transcriptomic analysis by Ingenuity Pathway Analysis (IPA) revealed that the SPINK1-metallothionein pathway is a top 1-repressed canonical signaling pathway by DDX3X. Furthermore, SPINK1 and the metallothionein gene family all serve as poor prognostic indicators, and the expression levels of those genes are inversely correlated with DDX3X in RCC. Furthermore, digoxin was identified via Connectivity Map analysis (L1000) for its capability to reverse gene signatures in patients with low DDX3X. Importantly, cancer cell proliferation and migration were decreased upon digoxin treatment in RCC cells. The results of this study indicate the significance of the DDX3Xlow/SPINK1high/metallothioneinhigh axis for predicting poor survival outcome in RCC patients and suggest digoxin as a precise and personalized compound for curing those patients with low DDX3X expression levels.

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“…Similar studies had similarly low sample size yet give significance in practice. Tiwari et al showed AR and its transcriptional co-repressor REST modulate SPINK1 expression, and plausible role of SPINK1 in the progression of Neuroendocrine prostate cancer with only few samples (30). Another study by Cheung et al, using only 11 samples per group founded that the Actin alpha cardiac muscle 1 (ACTC1) gene expression would play a role in compensating ADT administration for PCa as a response to ADT-induced muscle loss (31).…”

Section: Adtmentioning

confidence: 99%

Early upregulation of AR and steroidogenesis enzyme expressions after 3 months of androgen-deprivation therapy.

Hamid¹,

Putra

Sari

et al. 2020

Preprint

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Background: Androgen-Deprivation Therapy (ADT) is a standard treatment for advanced prostate cancer (PCa). However, there is a high recurrence or progression rate during ADT. Until now, there is no evidence on when the progression starts. This study would like to evaluate the early response of intraprostatic androgen receptor (AR) and steroidogenic enzyme gene expressions in ADT.Methods: Prostate tissue samples were taken from PCa patients with urinary retention, who had ADT (ADT- PCa; n=10), and further grouped into ≤12 months (n=4) and ADT >12 months (n=6). ADT-PCa group were then compared with BPH (n=12) and primary (no treatment) PCa tissues (n=16). AR and steroidogenic enzyme genes were extracted from Formalin Fixed Paraffin embedded (FFPE) tissues and analysed using rtPCR. Protein expressions were evaluated by immunohistochemistry of specific antibodies. Results: AR gene expression was found higher in ADT-PCa group compared to BPH and primary PCa. Both ADT ≤12 and > 12 months subgroups had significantly higher relative gene expression of AR (p 0.01 and 0.03) compared to primary PCa. AR protein expression in ADT-PCa group showed an increase trend in ADT ≤12 months subgroup and a significantly elevated expression AR protein in ADT >12 months subgroup compared with PCa (100%; p <0.01). Half (50%) of ADT ≤12 months patients were found to have upregulation of AR, and one undergone upregulation from only 3 months of ADT. A trend of elevating relative gene expression of SRD5A3 were also found within the groups given ADT. Conclusion: There are upregulation of AR and steroidogenic enzymes in ADT-PCa patients, as early as 3 months without showing PSA elevation. Steroidogenic enzyme, especially SRD5A3 expression was also showing upregulation before PSA rises.

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Androgen deprivation upregulates SPINK1 expression and potentiates cellular plasticity in prostate cancer

Cited by 67 publications

References 72 publications

Dynamics of Cellular Plasticity in Prostate Cancer Progression

Dynamics of Cellular Plasticity in Prostate Cancer Progression

DDX3X is Epigenetically Repressed in Renal Cell Carcinoma and Serves as a Prognostic Indicator and Therapeutic Target in Cancer Progression

Early upregulation of AR and steroidogenesis enzyme expressions after 3 months of androgen-deprivation therapy.

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