Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer

Patel, Rachana; Brzezinska, Elspeth A.; Repiščák, Peter; Ahmad, Imran; Mui, Ernest; Gao, Meiling; Blomme, Arnaud; Harle, Victoria; Tan, Ee Hong; Malviya, Gaurav; Mrowinska, Agata; Loveridge, Carolyn J.; Rushworth, Linda; Edwards, Joanne; Ntala, Chara; Nixon, Colin; Hedley, Ann; Mackay, Gillian; Tardito, Saverio; Leung, Hing Y.

doi:10.1158/0008-5472.can-19-1684

Cited by 37 publications

(48 citation statements)

References 45 publications

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“…At the same time, WNT/β-catenin signaling pathway is highly activated in AR negative PCa (Wan et al, 2012). A growing body of evidence supports the hypothesis that WNT/β-catenin signalling pathway promotes metastatic castration-resistant prostate cancer (mCRPC) by a complex interaction with AR signalling (Patel et al, 2020; Ramamurthy et al, 2018; Schweizer et al, 2008; Tsao et al, 2021). WNT/β-catenin axis is a known positive regulator of PCa metastatic dissemination (Patel et al, 2020) and treatment resistance (Yeh et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Gorodetska

Offermann

Pueschel

et al. 2021

Preprint

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Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and β-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease.

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Section: Discussionmentioning

confidence: 99%

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Gorodetska

Offermann

Pueschel

et al. 2021

Preprint

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“…In addition, AR is in fact a WNT/β-catenin target gene, and AR and β-catenin can directly interact and co-localize in the nucleus to mediate transcriptional activity of AR-regulated genes [ 328 , 329 , 330 ] ( Figure 1 ). WNT and AR signaling cascades have also been shown to reciprocally inhibit each other in murine prostate cancer [ 331 ].…”

Section: The Pi3k-akt-mtor Pathway Intersects With Multiple Oncogementioning

confidence: 99%

“…Mouse models have been instrumental in determining the role of WNT signaling in prostate cancer, and we and others have shown that constitutive activation of β-catenin or Apc bi-allelic deletion predisposes to prostate adenocarcinoma in mice [ 269 , 331 , 332 , 333 ]. Moreover, β-catenin activation can cooperate with Pten heterozygous or homozygous deletion to promote prostate cancer progression, CRPC transition and metastatic potential [ 269 , 331 , 332 , 333 ], indicating a synergistic relationship exists between the PI3K-AKT-mTOR and WNT cascades.…”

Section: The Pi3k-akt-mtor Pathway Intersects With Multiple Oncogementioning

confidence: 99%

“…WNT inhibitors are beginning to enter clinical trials, including small-molecule inhibitors to the enzyme porcupine that block WNT ligand secretion, such as WNT974 (LGK974) [ 320 , 322 ]. Preliminary data from a WNT974 phase 1 clinical trial (NCT01351103) for a small range of human malignancies (excluding prostate cancer) report a manageable safety profile and suppression of canonical WNT/β-catenin target gene AXIN2 [ 320 ], and recent preclinical studies have indicated that WNT974 treatment is efficacious against prostate cancer [ 331 , 365 ]. β-catenin has also been reported to facilitate resistance to PI3K and AKT inhibition in colon cancer [ 334 ].…”

Section: The Pi3k-akt-mtor Pathway Intersects With Multiple Oncogementioning

confidence: 99%

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The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

Shorning

Dass

Smalley

et al. 2020

IJMS

394

251

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Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.

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“…β-catenin activation and PTEN deletion synergistically drive non-AR independent castrationresistant prostate cancer. [24][25][26] In most cancer types, the PI3K signaling pathway is activated and promotes tumorigenesis by regulating nutrient metabolism, cell proliferation, survival, migration, and angiogenesis. 26 The potential mechanism of PI3K/AKT activation is mainly due to the deletion or mutation of its key negative regulatory gene, PTEN.…”

Section: Dovepressmentioning

confidence: 99%

<p>Identification of Critical Pathways and Hub Genes in LanCL1-Overexpressed Prostate Cancer Cells</p>

Tang

Lü

et al. 2020

OTT

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Background: Prostate cancer is one of the most common malignancies in urology, especially in developed countries. Our previous studies showed that Lanthionine synthase C-like protein 1 (LanCL1) can promote the proliferation of prostate cancer cells and protect cells from oxidative stress. Also, LanCL1 protects cells by inhibiting the JNK signaling pathway after H 2 O 2 treatment. Materials and Methods: In our study, we analyzed the data of RNA-seq to identify the DEGs after LanCL1 overexpression. We performed a functional enrichment analysis with gene set enrichment analysis (GSEA) and a database for annotation, visualization, and integrated discovery (DAVID). We also identified the critical hub gene correlated with disease prognosis by Cox regression analysis. Results: A total of 8928 DEGs were identified. Through the analysis of GO and KEGG, we found that DEGs are significantly enriched in categories related to metabolism, cancerrelated signaling pathways, and inflammation. The top 15 hub genes were then identified and ranked by degree from the protein-protein interaction network. Survival analysis showed 4 hub genes related to disease prognosis and ICAM1 expression is an independent risk factor for the prognosis. Conclusion: Our results suggest the critical genes and pathways that might play key roles after LanCL1 overexpression in prostate cancer. We also provide candidate gene targets that might play important roles in prostate cancer development.

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Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer

Cited by 37 publications

References 45 publications

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

<p>Identification of Critical Pathways and Hub Genes in LanCL1-Overexpressed Prostate Cancer Cells</p>

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