Abstract
Triple negative breast cancer (TNBC) features among the most aggressive manifestations of cancer due to its enhanced metastatic potential and immunity to therapeutics which target hormone receptors. Under such scenarios, anti-cancer compounds with an ability to influence multiple targets, or an entire process, will have an advantage over specific signal transduction inhibitors. To counter the metastatic threat it is essential to target cellular components central to the processes of cancer cell migration and adaptation. Our previous work on a novel triterpenoid, AECHL-1, explored its anti-cancer potential, and linked it to elevated ER stress in cancer cells, while its anti-angiogenic potential was credited for its ability to manipulate the cytoskeleton. Here, we broaden its range of action by showing that it curbs the metastatic ability of TNBC cells, both in vitro in MDA-MB-231 cell line and in vivo, in mouse models of metastasis. AECHL-1 does so by disrupting the cytoskeletal network, and also suppressing NF-κB and β-Catenin mediated key molecular pathways. These activities also contributed to AECHL-1 mediated suppression of TGF-β/TNF-α induced Epithelial to Mesenchymal Transition (EMT) and cancer stem cell characteristic. Thus, we present AECHL-1 as a promising therapeutic inhibitor of metastatic disease.
Highlights
Recently we gained further insights into its mechanism of action, and demonstrated that AECHL-1 could trigger apoptosis in breast cancer cells via mitochondrial perturbations and elevated ER stress[16]
Metastasis requires clusters of tumor cells to make their way through the protein dense ECM and subsequently invade extra-tumoral tissues, including the vascular and lymphatic systems
Our compound of interest, AECHL-1 was tested for its ability to interfere with this transformative process that tumor cells undergo in order to form metastatic lesions
Summary
Recently we gained further insights into its mechanism of action, and demonstrated that AECHL-1 could trigger apoptosis in breast cancer cells via mitochondrial perturbations and elevated ER stress[16]. Another line of investigation revealed that AECHL-1 inhibits tumor angiogenesis of breast cancer cells via cytoskeletal disruption[17]. Our findings demonstrate that AECHL-1 could inhibit cancer cell migration and invasion by targeting the processes of actin nucleation and branch formation, both in vitro and in vivo. AECHL-1 could execute these activities by down-regulating the expression of proteins such as β-catenin and NF-κB, which are engaged in regulation of the above mentioned processes, making AECHL-1 an effective dispenser of anti-cancer activities
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