Abstract
This study investigates the anticancer effect of dehydrocostuslactone (DHE), a plant-derived sesquiterpene lactone, on human breast cancer cells. DHE inhibits cell proliferation by inducing cells to undergo cell cycle arrest and apoptosis. DHE suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G(0)/G(1)-S phase arrest in MCF-7 cells. In contrast, DHE caused S-G(2)/M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. DHE induces up-regulation of Bax and Bad, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor and endonuclease G. We also found that DHE inhibits survival signaling through the Janus tyrosine kinase-signal transducer and activator of transcription-3 signaling by increasing the expression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell cycle progression and cell death through SOCS-1 and SOCS-3. Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer.
Highlights
Breast cancer is one of the most common human malignancies and the second leading cause of cancer-related deaths in women, and its incidence in the developing world is on the rise [1]
Because Suppressors of cytokine signaling (SOCS) is an inhibitor of STAT3, and STAT3 promotes cell cycle progression and cell survival resulting in cancer development [7, 10], we addressed the role of SOCS-1 and SOCS-3 in DHE-mediated cell cycle and apoptosis by specific genetic knockdown
The important findings from the present study are that DHE inhibits proliferation of human breast cancer cell lines and that this effect may be the consequence of cell cycle arrest and caspase-independent apoptosis
Summary
Breast cancer is one of the most common human malignancies and the second leading cause of cancer-related deaths in women, and its incidence in the developing world is on the rise [1]. Janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT) signaling has been shown to participate in various cellular processes, including immune function, cell proliferation, differentiation, survival, motility, and apoptosis [5, 6]. Abnormal activation of JAK/STAT3 signaling has been seen in multiple tumors including breast cancers [5]. Binding of specific ligands to cytokines receptors leads to receptor dimerization and cross-activation of receptor-associated JAK kinases, which in turn phosphorylates tyrosine, leading to changes of intercellular parts of receptors and subsequent activation of receptor-associated JAKs, followed by STAT docking and phosphorylation [6, 7]. SOCSs directly inhibit JAK kinases by binding to the receptor or to the JAK activation loop [7]. SOCS proteins compete with STATs for binding sites on the receptor by SH2 domains [8]. SOCS proteins can target the receptor complex and associated signaling proteins for proteasomal degradation through their SOCS boxes, which mediate interactions with elongins B
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