Androgen-independent LNCaP cells are a subline of LNCaP cells with a more aggressive phenotype and androgen suppresses their growth by inducing cell cycle arrest at the G1 phase

Abstract

Androgen deprivation therapy (ADT, surgical or chemical castration) is the mainstay treatment for metastatic prostate cancer (PCa); however, patients ineluctably relapse despite extremely low androgen levels. This evolution of PCa indicates its lethal progression. In this study, to mimic the traits of clinical PCa progression in vitro, we investigated the alterations in the cell biological characteristics in androgen-independent LNCaP cells (LNCaP-AI cells) compared with LNCaP cells. We also examined the effects of androgen on LNCaP and LNCaP-AI cell proliferation, androgen receptor (AR) expression and prostate-specific antigen (PSA) secretion. Furthermore, AR was silenced in the LNCaP and LNCaP-AI cells to detect the roles that AR plays in cell growth, apoptosis and PSA secretion. We found that prolonged androgen ablation increased the LNCaP-AI cell growth rate and cell invasiveness, and induced epithelial-mesenchymal transition in the LNCaP-AI cells. Moreover, despite the fact that the LNCaP and LNCaP-AI cells expressed equal amounts of AR protein, androgen induced a greater secretion of PSA in the LNCaP-AI cells than in the LNCaP cells. The proliferation of the LNCaP-AI cells was not dependent on, but was suppressed by androgen, which led to arrest at the G1 phase. Conversely, androgen significantly increased LNCaP cell proliferation by promoting the G1-S transition. Moreover, the silencing of AR suppressed LNCaP and LNCaP-AI cell growth by inducing cell cycle arrest at the G1 phase rather than promoting apoptosis, and reduced PSA secretion. On the whole, our data suggest that LNCaP-AI cells have a more more aggressive phenotype compared with the LNCaP cells; AR remains a critical factor in the LNCaP-AI cells, and androgen suppresses LNCaP-AI cell growth by blocking the cell cycle at the G1 phase.

Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors

“…Then, after a quiescent period of ADT adaptation of 2-3 weeks, androgen independent (AI) colonies begin to form. 6 An attractive strategy to prevent this process would be to bypass the cell cycle arrest via inhibition of ATM or ATR, causing the cells to undertake replication with damaged DNA that would cause mitotic catastrophe, a strategy that was in fact implemented in LNCaP treated concomitantly with bicalutamide and ATM inhibition. 4 But a limitation of this approach is how to make the inhibition of ATM or ATR specific to PCa cells.…”

Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer

“…Extended cell culture (several months) in androgen-depleted or AR antagonized conditions ultimately yielded androgen-independent or Enz-resistant CRPC cells that reinitiated proliferation [6, 8, 34, 35]. Our comparative signature scoring of transcriptomics data sets of relevant studies performed in cell culture leading to Enz resistance in LNCaP and C4-2B cells [26], in castrated mice progressing to primary and secondary CRPC after serial tumor xenograft transplantation of LAPC9 and LNCaP cells [27] and matching PCa tumors from patients before and after androgen deprivation therapy for 22 weeks [28] by GSVA using lipid metabolism related gene sets showed extensive concordance between cell culture models, pre-clinical tumor xenograft models and clinical samples of ATT resistance (Fig.…”

“…5G). Moreover, acquisition of fully developed therapy resistance is associated with reactivation of cell proliferation and enhanced metabolic activity and oxidative stress [6, 8, 34, 35], suggesting dynamic changes to ferroptosis sensitivity and a limited therapeutic window. Hence, we sought to identify inhibitors of metabolic pathways that both proliferating parental cells and quiescent persister cells were critically dependent on, promising a larger therapeutic window and limiting the likely effects of changes in the proliferation status on drug sensitivity.…”

“…Despite initial tumor regression following targeted cancer therapies, development of drug resistance and disease progression ultimately leading to patient death remain major clinical challenges of many pharmacological interventions in various types of cancer, including PCa. Previous studies of resistance to androgen receptor-targeted therapies (ATTs) in PCa analyzed models after extensive treatment periods (months to years) with fully developed resistance as indicated by reactivated cell proliferation [6, 8, 34, 35]. Different to these studies, we hypothesized that delineating early events of ATT-induced metabolic reprogramming might provide novel co-targets that could extend the efficacy of ATTs, thereby delaying therapy failure and disease progression to currently incurable CRPC and Enz-resistant CRPC.…”

Expression of endoplasmic reticulum mannosyl-oligosaccharide α1, 2-mannosidase regulates tumorigenicity of prostate cancer cells

“…Following the initial observation that overexpression of MAN1B1 alone in PC3 cells is sufficient to reduce cellular migratory behavior, we chose to analyze two additional PCa cell lines with low to moderate metastatic potential, including the androgen-dependent LNCaP cell line and androgen-independent LNCaP-AI cell line (32,33). Analysis of additional cell lines will help to establish the migration phenotype as a general result of MAN1B1 expression across several PCa cell lines.…”