Phenotypic characterization of two novel cell line models of castration‐resistant prostate cancer

Abstract

Background Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the investigation of resistance mechanisms and the assessment of drugs for the treatment of castration‐resistant prostate cancer. Methods We generated two novel cell line models (LAPC4‐CR and VCaP‐CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA‐seq) and proteomic analyses (SWATH‐MS) to delineate expression differences between castration‐sensitive and castration‐resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models. Results The two cell line derivatives LAPC4‐CR and VCaP‐CR showed castration‐resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High‐dose androgen treatment resulted in significant growth arrest of VCaP‐CR but not in LAPC4‐CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration‐resistant LNCaP‐abl cells revealed an expression signature of castration resistance. Conclusions The two novel cell line models LAPC4‐CR and VCaP‐CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance.

Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy

“…Both hormone sensitive cell lines, LNCaP and VCaP, demonstrate altered ORR responses to metabolic inhibitors after ADT compared to control conditions (Figure 4B,C). Responses demonstrate some variation between lines which is unsurprising due to their different genetic phenotypes 48 . LNCaP cells in FBS control conditions show altered ORR (normalized to the media control) for all metabolic inhibitors (Figure 4B).…”

“…Previous work has investigated AR antagonists after ADT and observed similar signaling responses, 6,33 here, we focus on targeted metabolic inhibitors. Differences in responses to metabolic inhibitors was noted between hormone‐sensitive cell lines, reflecting the genetic and perhaps epigenetic heterogeneity of PC 48,54 . Importantly, OMI of two hormone sensitive lines showed that ADT‐treated cells were resistant to several targeted metabolic inhibitors, most notably inhibition of FA metabolism.…”

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

“…Androgen treatment rapidly stimulates the transcription of hundreds to thousands of protein-encoding genes, but moreover, represses a number of genes, with a considerable overlap between different hormone-dependent prostate cancer cell lines [ 85 , 167 , 168 , 169 ]. A number of non-coding transcripts are also directly regulated by the AR [ 149 ].…”

Serum levels of chromogranin are not predictive of poorly differentiated prostate cancer: Results from a multicenter radical prostatectomy cohort

“…Chromogranin A (CgA) is an acidic glycoprotein commonly expressed in all neuroendocrine cells and serum levels are increased in patients with neuroendocrine tumors 7 . Neuroendocrine activity can also be detected in prostate cancer as a marker of its neuroendocrine differentiation; more specifically, CgA levels are elevated in castration‐resistant PCa patients 8–11 …”

“…7 Neuroendocrine activity can also be detected in prostate cancer as a marker of its neuroendocrine differentiation; more specifically, CgA levels are elevated in castrationresistant PCa patients. [8][9][10][11] In recent years, the prognostic capacity of CgA as a biomarker for PCa has been extensively evaluated. Hong et al in their recent meta-analysis indicated that having high CgA levels represents an independent predictor of worse overall survival (OS) and progression-free survival (PFS) in castration-resistant prostate cancer (CRPC) patients.…”