Research ArticleMitosis

Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression

See allHide authors and affiliations

Sci. Signal.  28 Mar 2017:
Vol. 10, Issue 472, eaah4007
DOI: 10.1126/scisignal.aah4007

You are currently viewing the abstract.

View Full Text

Sphingolipids stimulate mitosis

Drugs that attempt to halt the increased rate of cell division or mitosis in tumors are usually toxic to healthy cells as well. Thus, identifying a more cancer-specific target that promotes cell division may be more effective and may have fewer side effects. Andrieu et al. found that the kinase SphK1 and its lysophospholipid product (S1P) stimulated mitosis through a pathway that is associated with cell proliferation. Both SphK1 and S1P are increased in abundance in many cancer types, and drugs that target the downstream pathway are in clinical trials. The findings reveal an unexpected potential therapeutic target to limit tumor cell proliferation.

Abstract

Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein–coupled receptors (S1P1–5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis. Increasing the abundance of S1P promoted mitotic progression, overrode the spindle assembly checkpoint (SAC), and led to chromosome segregation defects. S1P was secreted through the transporter SPNS2 and stimulated mitosis by binding to and activating S1P5 on the extracellular side, which then activated the intracellular phosphatidylinositol 3-kinase (PI3K)–AKT pathway. Knockdown of S1P5 prevented the S1P-induced spindle defect phenotype. RNA interference assays revealed that the mitotic kinase Polo-like kinase 1 (PLK1) was an important effector of S1P-S1P5 signaling-induced mitosis in HeLa cells. Our findings identify an extracellular signal and the downstream pathway that promotes mitotic progression and may indicate potential therapeutic targets to inhibit the proliferation of cancer cells.

View Full Text