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

• DOI: 10.1038/onc.2017.342
• Publication Date: 2017-09-19T06:44:04Z
• Authors: L Xia; X Xiao; W L Liu; Y Song; T J J Liu; Y J Li; E Zacksenhaus; X J Hao; Y Ben-David
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; 0301 basic medicine; MAP Kinase Signaling System; Breast Neoplasms; Mice, SCID; Transforming Growth Factor beta1; Mice; 03 medical and health sciences; Animals; Humans; Genes, Tumor Suppressor; RNA, Small Interfering; 10. No inequality; 2. Zero hunger; Mice, Inbred BALB C; 0303 health sciences; Interleukins; Microfilament Proteins; Membrane Proteins; Rats; 3. Good health; HEK293 Cells; Gene Knockdown Techniques; MCF-7 Cells; Female; Carrier Proteins

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 p21cip1. 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.