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Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G₁ arrest independent of DRD2.

ABSTRACT: Thioridazine is an antipsychotic that has been shown to induce cell death and inhibit self-renewal in a broad spectrum of cancer cells. The mechanisms by which these effects are mediated are currently unknown but are presumed to result from the inhibition of dopamine receptor 2 (DRD2). Here we show that the self-renewal of several, but not all, triple-negative breast cancer cell lines is inhibited by thioridazine. The inhibition of self-renewal by thioridazine in these cells is mediated by DRD2 inhibition. Further, we demonstrate that DRD2 promotes self-renewal in these cells via a STAT3- and IL-6-dependent mechanism. We also show that thioridazine induces a G₁ arrest and a loss in cell viability in all tested cell lines. However, the reduction in proliferation and cell viability is independent of DRD2 and STAT3. Our results indicate that although there are cell types in which DRD2 inhibition results in inhibition of STAT3 and self-renewal, the dramatic block in cancer cell proliferation across many cell lines caused by thioridazine treatment is independent of DRD2 inhibition.

SUBMITTER: Tegowski M

PROVIDER: S-EPMC6187640 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G<sub>1</sub> arrest independent of DRD2.

Tegowski Matthew M Fan Cheng C Baldwin Albert S AS

The Journal of biological chemistry 20180821 41

Thioridazine is an antipsychotic that has been shown to induce cell death and inhibit self-renewal in a broad spectrum of cancer cells. The mechanisms by which these effects are mediated are currently unknown but are presumed to result from the inhibition of dopamine receptor 2 (DRD2). Here we show that the self-renewal of several, but not all, triple-negative breast cancer cell lines is inhibited by thioridazine. The inhibition of self-renewal by thioridazine in these cells is mediated by DRD2 ...[more]

PMID: 30131338

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Project description:Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation. These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells.

Dataset Information

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G₁ arrest independent of DRD2.

Publications

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G<sub>1</sub> arrest independent of DRD2.

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Dataset Information

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2.

Publications

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G<sub>1</sub> arrest independent of DRD2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G₁ arrest independent of DRD2.