Numb−/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling

Abstract

To elucidate the role and molecular mechanism of Numb in prostate cancer and the functional contribution of Numb prostate cancer cells in castration resistance. The expression of Numb was assessed using multiple datasets and prostate cancer tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human prostate cancer cell lines were investigated and In addition, we developed a reliable approach to distinguish between prostate cancer cell populations with a high or low endogenous expression of Numb protein using a Numb promoter-based lentiviral reporter system. The difference between Numb and Numb prostate cancer cells in the response to androgen-deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting, and quantitative real-time PCR. We show here that Numb was downregulated and negatively correlated with prostate cancer advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and castration-resistant prostate cancer development by suppressing Notch and Hedgehog signaling. Using a promoter-based lentiviral reporter system, we were able to distinguish Numb prostate cancer cells from Numb cells. Numb prostate cancer cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell-associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb cells in response to ADT. Numb enriches a castration-resistant prostate cancer cell subpopulation that is associated with unregulated Notch and Hedgehog signaling. .

Prostate Stem Cells and Cancer Stem Cells

“…Interestingly, asymmetric divisions in which PSA −/low cells generate a PSA + daughter also showed differential segregation of Numb (Qin et al 2012), a putative cell fate determinant that has been implicated in asymmetric divisions in multiple systems (Bajaj et al 2015). Consistent with this finding, Numb −/low cells isolated from a range of prostate cancer cell lines had increased tumor initiation relative to Numb + cells, and displayed greater castration resistance (Guo et al 2017).…”

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

“…For advanced and metastatic prostate cancer, the therapeutic focus has largely revolved around androgen deprivation therapy (ADT) which usually achieves short-term effectiveness but ultimately induces drug resistance and metastasis 10,31 . Increasing evidence has indicated that ADT induces the enrichment of PCSCs subpopulation, which are resistant to traditional killing strategies and drive subsequent metastasis [32][33][34] . Therefore, eliminating PCSCs is crucial for improving the clinical outcomes of prostate cancer.…”

“…To date, approximately 50 chemokines have been identified 46 and several TAMs-derived chemokines have been reported to be associated with cancer progression and metastasis. For example, it has been reported that TAMs could promote prostate cancer migration through activation of the CCL22-CCR4 axis 32 . TAMs released CCL18 to further promote the aggressive phenotype of breast phyllodes tumors by enhancing and maintaining the myofibroblast differentiation and invasion in vitro and in vivo 23 .…”

Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer

“…Androgen deprivation therapy (ADT), when applied to advanced and recurrent prostate cancers, achieves short-term effectiveness, but ultimately induces drug resistance, leading to increased cancer-related deaths (6,7). Increasing evidence has indicated that ADT induces reprogramming of prostate cancer and enriches a subpopulation of cells with CSC properties, which are resistant to ADT and drive prostate cancer progression (8,9). Therefore, eliminating CSCs may be crucial for achieving a good response of prostate cancer to ADT.…”