Tumorigenic Potential of Transit-Amplifying Prostate Cells

The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer.

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Distinct roles for the RNA-binding protein Staufen1 in prostate cancer

BMC Cancer ◽

10.1186/s12885-021-07844-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kristen A. Marcellus ◽

Tara E. Crawford Parks ◽

Shekoufeh Almasi ◽

Bernard J. Jasmin

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Rna Binding ◽

Prostate Cancer Cell ◽

Rna Binding Protein ◽

Migration And Invasion ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Prostate Cells

Abstract Background Prostate cancer is one of the most common malignant cancers with the second highest global rate of mortality in men. During the early stages of disease progression, tumour growth is local and androgen-dependent. Despite treatment, a large percentage of patients develop androgen-independent prostate cancer, which often results in metastases, a leading cause of mortality in these patients. Our previous work on the RNA-binding protein Staufen1 demonstrated its novel role in cancer biology, and in particular rhabdomyosarcoma tumorigenesis. To build upon this work, we have focused on the role of Staufen1 in other forms of cancer and describe here the novel and differential roles of Staufen1 in prostate cancer. Methods Using a cell-based approach, three independent prostate cancer cell lines with different characteristics were used to evaluate the expression of Staufen1 in human prostate cancer relative to control prostate cells. The functional impact of Staufen1 on several key oncogenic features of prostate cancer cells including proliferation, apoptosis, migration and invasion were systematically investigated. Results We show that Staufen1 levels are increased in all human prostate cancer cells examined in comparison to normal prostate epithelial cells. Furthermore, Staufen1 differentially regulates growth, migration, and invasion in the various prostate cancer cells assessed. In LNCaP prostate cancer cells, Staufen1 regulates cell proliferation through mTOR activation. Conversely, Staufen1 regulates migration and invasion of the highly invasive, bone metastatic-derived, PC3 prostate cells via the activation of focal adhesion kinase. Conclusions Collectively, these results show that Staufen1 has a direct impact in prostate cancer development and further demonstrate that its functions vary amongst the prostate cancer cell types. Accordingly, Staufen1 represents a novel target for the development of much-needed therapeutic strategies for prostate cancer.

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New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer

Genes ◽

10.3390/genes12050723 ◽

2021 ◽

Vol 12 (5) ◽

pp. 723

Author(s):

Munazza Ahmed ◽

Grace Hope Daoud ◽

Asmaa Mohamed ◽

Rania Harati

Keyword(s):

Breast Cancer ◽

Dna Sequence ◽

Gene Editing ◽

Causes Of Death ◽

Breast Cancer Treatment ◽

Delivery Methods ◽

Therapeutic Applications ◽

Tumorigenic Potential ◽

Its Gene ◽

Shed Light

Breast cancer is one of the most prevalent forms of cancer globally and is among the leading causes of death in women. Its heterogenic nature is a result of the involvement of numerous aberrant genes that contribute to the multi-step pathway of tumorigenesis. Despite the fact that several disease-causing mutations have been identified, therapy is often aimed at alleviating symptoms rather than rectifying the mutation in the DNA sequence. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 is a groundbreaking tool that is being utilized for the identification and validation of genomic targets bearing tumorigenic potential. CRISPR/Cas9 supersedes its gene-editing predecessors through its unparalleled simplicity, efficiency and affordability. In this review, we provide an overview of the CRISPR/Cas9 mechanism and discuss genes that were edited using this system for the treatment of breast cancer. In addition, we shed light on the delivery methods—both viral and non-viral—that may be used to deliver the system and the barriers associated with each. Overall, the present review provides new insights into the potential therapeutic applications of CRISPR/Cas9 for the advancement of breast cancer treatment.

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