The role of the S1P3 receptor in inflammation-associated proliferative disorders

Filipenko, Iuliia; Huwiler, Andrea (2016). The role of the S1P3 receptor in inflammation-associated proliferative disorders (Submitted). (Dissertation, Graduate School for Cellular and Biomedical Sciences, University of Bern, Faculty of Medicine)

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Inflammation is involved in the pathogenesis of many different disorders,
including glomerulonephritis, fibrosis and cancer. Unraveling the regulatory
mechanisms underlying the molecular processes of inflammation remains
crucial for the development of novel therapeutics for future treatment of
inflammatory disorders.
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid molecule,
which likely plays an important role in inflammation. However, the molecular
mechanisms involved in S1P-mediated inflammation are still not completely
understood. This work aimed to unravel the interconnection between S1P and
other molecular players implicated in inflammatory response, as well as to
indicate the S1P receptor subtype the activation of which contributes to
proliferation and migration of non-cancerous cells and to metastatic progression
of breast cancer. In addition, the therapeutic potential of drugs targeting early
steps of the inflammatory response was assessed.
As model systems for the non-cancerous studies we used renal mesangial
cells (rMC) and mouse embryonic fibroblasts (MEF), and for the cancer studies
the breast cancer cell line MDA-MB-231 and two metastatic sublines derived
from lung (4175) and bone (1833).
Our data demonstrate that the S1P3 receptor is strongly upregulated in
lung and bone metastatic cell lines compared to the parental MDA-MB-231
cells, and its activation by S1P has pro-inflammatory, pro-migratory and pro
invasive potential by inducing COX-2 expression and PGE2 signaling via EP2
and EP4. These data were confirmed in non-cancerous studies, where we found
that S1P3 receptor is upregulated in mMC and MEFs upon the loss of SphK2.
Our results show that the deficiency of SphK2 in these cells correlates with an
enhanced proliferative and migratory capacity, indicating that SphK2 exerts
suppressive effects on cell growth and migration. This finding is likely to be due

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to the enhanced expression of S1P3, as its depletion in mesangial cells reduced
their proliferation and migration rate.
Our next study revealed that the novel cPLA2 inhibitors AVX001 and
AVX002 have an anti-inflammatory potential in cultures of rMC by reducing the pro-inflammatory mediator PGE2 through the inhibitory effect on NFκB
activation. Thus, they represent promising novel drugs for the treatment of
inflammatory disorders.
Altogether, our data demonstrate for the first time a critical role of the
S1P3 receptor in S1P-mediated proliferative and inflammatory responses, and
identify S1P3 as a potential target for therapeutic intervention to treat
inflammation-associated proliferative disorders.

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