Dopamine receptor antagonists induce differentiation of PC‐3 human prostate cancer cell‐derived cancer stem cell‐like cells

Abstract

Background The objective of this study was to determine whether PC‐3 human prostate cancer cell‐derived cancer stem cells (CSC)‐like cells grown in a regular cell culture plate not coated with a matrix molecule might be useful for finding differentiation‐inducing agents that could alter properties of prostate CSC. Methods Monolayer cells prepared from sphere culture of PC‐3 cells were characterized for the presence of pluripotency and tumorigenicity. They were then applied to screen a compound library to find compounds that could induce morphology changes of cells. Mechanisms of action of compounds selected from the chemical library that induced the loss of pluripotency of cells were also investigated. Results C5A cells prepared from PC‐3 cell‐derived sphere culture expressed pluripotency markers such as Oct4, Sox2, and Klf4. C5A cells were highly proliferative. They were invasive in vitro and tumorigenic in vivo. Some dopamine receptor antagonists such as thioridazine caused reduction of pluripotency markers and tumorigenicity. Thioridazine, unlike promazine, inhibited phosphorylation of AMPK in a dose dependent manner. BML‐275, an AMPK inhibitor, also induced differentiation of C5A cells as seen with thioridazine whereas A769663, an AMPK activator, blocked its differentiation‐inducing ability. Transfection of C5A cells with siRNAs of dopamine receptor subtypes revealed that knockdown of DRD2 or DRD4 induced morphology changes of C5A cells. Conclusions Some dopamine receptor antagonists such as thioridazine can induce differentiation of CSC‐like cells by inhibiting phosphorylation of AMPK. Binding to DRD2 or DRD4 might have mediated the action of thioridazine involved in the differentiation of CSC‐like cells.

Identification of a novel competing endogenous RNA network linked to the prognosis of prostate cancer

“…Recently, they suggested that dopamine receptor agonists resulted in lower viability of PC3 and LNCaP cells in vitro and indicated a potential role of DR signaling in PCa [36]. Su et al suggested that DR antagonists could inhibit AMPK phosphorylation, which promotes the differentiation of PCa cancer stem-like cells [37]. In our study, low DRD5 expression was positively associated with poor prognosis in patients with PCa.…”

WDR3 promotes stem cell‐like properties in prostate cancer by inhibiting USF2‐mediated transcription of RASSF1A

“…In recent years, the rise of cancer stem cells theory provides a novel idea for cancer treatment 6–8 . In PCa, stem cell‐like property is not only involved in cancer recurrence and metastasis, but also causes chemical resistance 9,10 . Because the growth of stem cells is related to multiple signaling pathways, targeting these signaling pathways will become an important research direction for the radical treatment of PCa in the future 11,12 .…”

“…[6][7][8] In PCa, stem cell-like property is not only involved in cancer recurrence and metastasis, but also causes chemical resistance. 9,10 Because the growth of stem cells is related to multiple signaling pathways, targeting these signaling pathways will become an important research direction for the radical treatment of PCa in the future. 11,12 However, the pathways that promote the development of prostate cancer stem cells still need to be further studied.…”

Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors

“…The mechanism by which thioridazine induces the differentiation of CSCs is largely unknown; however, a recent study demonstrated that thioridazine elevates cAMP levels in AML progenitor cells through DRD2 engagement, which induces cell maturation [ 71 ]. Additionally, thioridazine induces the differentiation of prostate CSCs by inhibiting the phosphorylation of AMPK [ 72 ]. A better understanding of the mechanism through which thioridazine induces EC cell differentiation may allow for a more targeted approach.…”