Coactosin-like protein CLP/Cotl1 suppresses breast cancer growth through activation of IL-24/PERP and inhibition of non-canonical TGFβ signaling

Abstract

Coactosin-like protein (CLP, or Cotl1), is an F-actin-binding protein, whose role in cancer is largely unknown. Here we show that CLP/Cotl1 is highly expressed in a rat epithelial breast cancer cell line (FE1.3) compared with its mesenchymal counterpart (FE1.2). Knockdown of CLP/Cotl1 in FE1.3 cells increased cell proliferation, whereas its overexpression in FE1.2 cells inhibited proliferation in culture and reduced tumor growth in xenograft assays in mice. Mechanistically, we identified two major pathways through which CLP/Cotl1 exerts its suppressive effects. First, CLP/Cotl1 re-expression in FE1.2 and in human MCF7 breast cancer cells induced expression of the growth-suppressor gene interleukin-24 (IL-24), which independently of p53 upregulates the tumor-suppressor genes p53 apoptosis effector related to PMP-22 (PERP) and p21. Second, overexpression of CLP/Cotl1 potentiated the growth-suppressive effect of transforming growth factor-β1 (TGFβ1), leading to downregulation of TGFβ-responsive genes vascular growth factor A/B (VEGFA/VEGFB), hypoxia inducing factor 1α (HIF-1α) and trombospondin 1 (TSP1), which mediate various hallmarks of cancer progression including angiogenesis, invasion and metastasis. CLP/Cotl1 inhibited TGFβ signaling via a non-canonical signaling involving IL-24-instigated inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) phosphorylation and subsequent post-transcriptional downregulation of SMAD2 and SMAD4. We also showed that CLP/COTL1 expression sensitizes breast cancer cells to chemotherapeutic drugs, and this was further enhanced by addition of exogenous TGFβ1. CLP/Cotl1 expression is lost in many human malignancies including prostate, uterine and breast cancers. Thus, our results uncover a novel tumor-suppressor role for CLP/Cotl1 and identify the downstream effectors interleukin 24 (IL-24)/PERP and IL-24/MAPK/ERK/TGFβ as potential targets for precision therapy.

CCL19 suppresses angiogenesis through promoting miR-206 and inhibiting Met/ERK/Elk-1/HIF-1α/VEGF-A pathway in colorectal cancer

“…Previous studies have shown that HIF-1α and VEGF-A can be induced through ERK1/2, PI3K/AKT, STAT3, and JNK pathways 19 – 22 . Thus, we also analyzed the expression of these proteins in tumor cell supernatant pre-treated HUVECs, and the results showed that low levels of pERK and pAKT were observed in HUVEC-SW1116/CCL19-CM compared with HUVEC-SW1116/Vector-CM, as well as high levels of pERK and pAKT were found in HUVEC-SW620/sh-CCL19-CM compared with HUVEC-SW620/sh-NC-CM (Fig.…”

<p>Coactosin-Like Protein (COTL1) Promotes Glioblastoma (GBM) Growth in vitro and in vivo</p>

“… 25 CLP/COTL1 is highly expressed in a rat epithelial breast cancer cell line (FE1.3) compared with its mesenchymal counterpart (FE1.2). 19 Knockdown of COTL1 in FE1.3 cells promoted cell proliferation, whereas its overexpression in FE1.2 cells inhibited proliferation and reduced tumor growth in xenograft assays. 19 Therefore, we speculated that COTL1 might be important in GBM progression.…”

“… 19 Knockdown of COTL1 in FE1.3 cells promoted cell proliferation, whereas its overexpression in FE1.2 cells inhibited proliferation and reduced tumor growth in xenograft assays. 19 Therefore, we speculated that COTL1 might be important in GBM progression. By conducting colony formation and MTT assays, we observed COTL1 inhibited GBM cell proliferation.…”

“… 17 , 18 In breast cancer, COTL1 suppressed cancer growth by activating IL-24/PERP and inhibiting non-canonical TGFβ signaling. 19 Though there are wide effects of COTL1 in cancer progression, its possible role in GBM remains unclear.…”

Transforming growth factor beta 1 polymorphisms and haplotypes associated with breast cancer susceptibility: A case-control study in Tunisian women

“…11,12 It was described to act as tumor suppressor in early carcinogenesis by inducing apoptosis or inhibiting cell growth, while promoting tumorigenicity and metastasis through suppression of local immunosurveillance and supporting tumor progression in advanced stages of cancer. 13,14 Located on chromosome 19 (19q13.1), TGFB1 gene contains several functional and non-functional polymorphisms, some of which were shown to contribute to altered BC susceptibility. 7,[15][16][17][18] Of these, rs1800469 (-1347C.T) promoter, rs1800470 (+29T.C) codon 10, and rs1800471 (+74G.C) signal peptide sequence variants were widely studied in BC.…”