TY - JOUR
T1 - SCN5A promotes the growth and lung metastasis of triple-negative breast cancer through EF2-kinase signaling
AU - Erdogan, Mumin Alper
AU - Yuca, Erkan
AU - Ashour, Ahmed
AU - Gurbuz, Nilgun
AU - Sencan, Sevide
AU - Ozpolat, Bulent
N1 - Funding Information:
This work was supported by the The Scientific and Technological Research Council of Turkey (TUBITAK)-2214 International Research Scholarship Program.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2023/1/15
Y1 - 2023/1/15
N2 - Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer often associated with early metastasis, poor prognosis, and shortened survival. The main causes of its high mortality level are attributed to significant genetic heterogenity, rapid development of chemoresistance, and a limited number of targeted therapeutics. Therefore, as described herein, we investigated the role of the SCN5A gene encoding the voltage-gated sodium ion channel NaV1.5 in vitro and in vivo in TNBC models. Cell proliferation, colony formation, invasion, western blot and in vivo analyzes were performed. We found that SCN5A gene/NaV1.5 and its neonatal spliced isoform nNaV1.5 were markedly upregulated in TNBC cells and that they promoted cell proliferation, colony formation, motility/migration, and invasion. Therapeutic targeting of NaV1.5/nNaV1.5 via systemic injection of specific siRNAs incorporated in single-lipid nanoparticles suppressed tumor growth and lung metastasis in orthotopic TNBC models. We further demonstrated that targeting of NaV1.5/nNaV1.5 expression associated with eukaryotic elongation factor-2 kinase (EF2K) expression. This approach led to the inhibition EF2K's oncogenic signaling and its clinically significant downstream targets, including integrin β1/Src/focal adhesion kinase, c-myc, cyclin D1, phosphoinositide 3-kinase/Akt, p-ERK, p-IF2α and p-PI3K. Targeting of NaV1.5/nNaV1.5 also induced robust apoptosis in TNBCs in vivo. Inhibition of both isoforms of SCN5A in TNBC cells enhanced the effect of first-line chemotherapeutics such as paclitaxel. In conclusion, our results provide the first evidence that expression of SCN5A has an important role in the growth of primary and lung-metastatic TNBCs and that targeting of NaV1.5/nNaV1.5 by systemically administered therapeutics is a potential molecularly targeted strategy to control TNBC progression and may enhance the efficacy of currently used chemotherapeutics.
AB - Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer often associated with early metastasis, poor prognosis, and shortened survival. The main causes of its high mortality level are attributed to significant genetic heterogenity, rapid development of chemoresistance, and a limited number of targeted therapeutics. Therefore, as described herein, we investigated the role of the SCN5A gene encoding the voltage-gated sodium ion channel NaV1.5 in vitro and in vivo in TNBC models. Cell proliferation, colony formation, invasion, western blot and in vivo analyzes were performed. We found that SCN5A gene/NaV1.5 and its neonatal spliced isoform nNaV1.5 were markedly upregulated in TNBC cells and that they promoted cell proliferation, colony formation, motility/migration, and invasion. Therapeutic targeting of NaV1.5/nNaV1.5 via systemic injection of specific siRNAs incorporated in single-lipid nanoparticles suppressed tumor growth and lung metastasis in orthotopic TNBC models. We further demonstrated that targeting of NaV1.5/nNaV1.5 expression associated with eukaryotic elongation factor-2 kinase (EF2K) expression. This approach led to the inhibition EF2K's oncogenic signaling and its clinically significant downstream targets, including integrin β1/Src/focal adhesion kinase, c-myc, cyclin D1, phosphoinositide 3-kinase/Akt, p-ERK, p-IF2α and p-PI3K. Targeting of NaV1.5/nNaV1.5 also induced robust apoptosis in TNBCs in vivo. Inhibition of both isoforms of SCN5A in TNBC cells enhanced the effect of first-line chemotherapeutics such as paclitaxel. In conclusion, our results provide the first evidence that expression of SCN5A has an important role in the growth of primary and lung-metastatic TNBCs and that targeting of NaV1.5/nNaV1.5 by systemically administered therapeutics is a potential molecularly targeted strategy to control TNBC progression and may enhance the efficacy of currently used chemotherapeutics.
KW - EF2-kinase
KW - Metastasis
KW - Na1.5 channel
KW - Oncogene
KW - siRNA
KW - Triple-negative breast cancer
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U2 - 10.1016/j.lfs.2022.121282
DO - 10.1016/j.lfs.2022.121282
M3 - Article
C2 - 36526045
AN - SCOPUS:85144343616
SN - 0024-3205
VL - 313
JO - Life Sciences
JF - Life Sciences
M1 - 121282
ER -