Lysophosphatidic Acid Promotes the Expansion of Cancer Stem Cells via TRPC3 Channels in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines. In this study, we have investigated additional lipid receptors upregulated in BCSCs. We found that lysophosphatidic acid (LPA) receptor 3 was highly expressed in ALDH-positive TNBC cells. The LPAR3 antagonist inhibited the increase in ALDH-positive cells after LPA treatment. Mechanistically, the LPA-induced increase in ALDH-positive cells was dependent on intracellular calcium ion (Ca2+), and the increase in Ca2+ was suppressed by a selective inhibitor of transient receptor potential cation channel subfamily C member 3 (TRPC3). Moreover, IL-8 production was involved in the LPA response via the activation of the Ca2+-dependent transcriptional factor nuclear factor of activated T cells. Taken together, our findings provide new insights into the lipid-mediated regulation of BCSCs via the LPA-TRPC3 signaling axis and suggest several potential therapeutic targets for TNBC.

Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

“…Recent reports have provided additional support for IL-8 s role in TNBC progression. These studies implicate IL-8 in the development of bone, brain, and lung metastasis [33][34][35], epithelial mesenchymal transition [36], and expansion of cancer stem cells [37]. Our current findings indicate that only the EDA domain of fibronectin activated NFκB signaling and cytokine release in MDA-MB-468 cells, while both the EDA and III-1c domains elicited the response in MDA-MB-231 cells.…”

Effects of cigarette smoke extract derived from heated tobacco products on the proliferation of lung cancer stem cells

“…The ALDEFLUOR kit (Stem Cell Technologies, Vancouver, BC, Canada) was used to detect CSC populations with high ALDH enzyme activity as was previously reported [12] . The cells were plated at a density of 1 × 10 5 cells in 60 mm culture dishes.…”

“…The sphere-forming assay was performed as previously described [12] . Briefly, cells were plated on ultra-low attachment 24-well plates (Corning, Acton, MA, USA) at a density of 5000 cells/mL in serum-free DMEM supplemented with N 2 (Gibco), 20 ng/mL basic fibroblast growth factor (R&D Systems, Minneapolis, MN, USA), and each concentration of the CSE.…”

TRP Channels as Molecular Targets to Relieve Endocrine-Related Diseases

“…Therefore, inhibition of the TRPC1-STIM1 complex may be an attractive target for the treatment of breast cancer metastasis. Naoya et al found that LPA/LPAR3 signaling and subsequent TRPC3 activation leaded to an increase in the number of breast cancer stem cells (BCSCs) through calcium-dependent transcriptional activation of IL-8 by NFAT ( Hirata et al, 2022 ). Polyunsaturated fatty acids (PUFA) and TRPC3 antagonists continuously inhibit the proliferation and migration of breast cancer cells ( Zhang et al, 2012b ), but the mechanism is still unclear.…”