LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1.
Parmanand MalviRadoslav JanostiakSuresh ChavaPadmini ManraiEsther YoonKamaljeet SinghMalini HarigopalRomi GuptaNarendra WajapeyeePublished in: Oncogenesis (2020)
Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype and due to the lack of hormone receptors and HER2 expression, TNBC has limited therapeutic options with chemotherapy being the primary choice for systemic therapy. LIM Domain Kinase 2 (LIMK2) is a serine/threonine kinase that plays an important role in the regulation of actin filament dynamics. Here, we show that LIM domain kinase 2 (LIMK2) is overexpressed in TNBC, and short-hairpin RNA (shRNA)-mediated LIMK2 knockdown or its pharmacological inhibition blocks metastatic attributes of TNBC cells. To determine the mechanism by which LIMK2 promotes TNBC metastatic progression, we performed stable isotope labeling by amino acids in cell culture (SILAC) based unbiased large-scale phosphoproteomics analysis. This analysis identified 258 proteins whose phosphorylation was significantly reduced due to LIMK2 inhibition. Among these proteins, we identified SRSF protein kinase 1 (SRPK1), which encodes for a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. We show that LIMK2 inhibition blocked SRPK1 phosphorylation and consequentially its activity. Furthermore, similar to LIMK2, genetic inhibition of SRPK1 by shRNAs or its pharmacological inhibition blocked the metastatic attributes of TNBC cells. Moreover, the pharmacological inhibition of LIMK2 blocked metastatic progression in mice without affecting primary tumor growth. In sum, these results identified LIMK2 as a facilitator of distal TNBC metastasis and a potential target for preventing TNBC metastatic progression.
Keyphrases
- protein kinase
- squamous cell carcinoma
- small cell lung cancer
- induced apoptosis
- nitric oxide
- metastatic breast cancer
- type diabetes
- genome wide
- dna methylation
- stem cells
- minimally invasive
- skeletal muscle
- cell proliferation
- insulin resistance
- risk assessment
- endoplasmic reticulum stress
- rectal cancer
- long non coding rna
- high fat diet induced
- human health