FTY720 Inhibits Expansion of Breast Cancer Stem Cells via PP2A Activation

Naoya Hirata1,2, Shigeru Yamada1,2, Shota Yanagida1,3

  • 1Division of Pharmacology, National Institute of Health Sciences, Kanagawa 210-9501, Japan.

Insights

The drug FTY720 effectively targets breast cancer stem cells (CSCs) by inhibiting their proliferation and stemness. This study highlights FTY720 as a potential therapeutic agent for breast cancer treatment.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Pharmacology

Background:

  • Breast cancer may originate from cancer stem cells (CSCs), identified by aldehyde dehydrogenase (ALDH) activity.
  • Novel therapeutics targeting CSCs are needed for effective breast cancer treatment.
  • Drug repositioning offers a promising avenue for discovering new CSC-targeting drugs.

Purpose of the Study:

  • To investigate the efficacy of FTY720, an inhibitor of sphingosine kinase 1 (SphK1), against breast cancer stem cells (CSCs).
  • To evaluate FTY720's impact on CSC proliferation, mammosphere formation, and stem cell marker expression.

Main Methods:

  • Utilized aldehyde dehydrogenase (ALDH) activity-based flow cytometry to identify and analyze CSCs.
  • Assessed the effect of FTY720 on CSC proliferation and mammosphere formation in vitro.
  • Measured the expression levels of stem cell markers (Oct3/4, Sox2, Nanog) and protein phosphatase 2A (PP2A).

Main Results:

  • FTY720 significantly inhibited the proliferation of ALDH-positive breast CSCs.
  • FTY720 treatment reduced mammosphere formation, a measure of stem cell self-renewal.
  • FTY720 decreased the expression of key stem cell markers by upregulating PP2A.

Conclusions:

  • FTY720 demonstrates potent anti-cancer stem cell activity in vitro.
  • FTY720 shows potential as a therapeutic drug for targeting breast CSCs.
  • The findings support FTY720 as a repositioned drug candidate for breast cancer therapy.

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.0K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.1K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.7K
Cancer Stem Cells and Tumor Maintenance02:40

Cancer Stem Cells and Tumor Maintenance

Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
5.1K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.2K