IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3′-diindolylmethane in ovarian cancer cells

Abstract

From our data we conclude that DIM exhibits an anti-IL6-like activity by inhibiting p-STAT3 enhanced ovarian cancer cell proliferation and in vitro metastasis-associated events, i.e., adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were found to act as targets of DIM. This anti-IL6-like property of DIM may pave the way for the development of novel ovarian cancer preventive and/or therapeutic strategies.

Role of interleukin-6 in cancer progression and therapeutic resistance

“…Activation of the IL-6/STAT-3 signalling axis is an important event in cancer which promotes tumorigenesis by regulating multiple survival signalling pathways in cancer cells [24]. IL-6 regulates nearly all hallmarks of cancer, such as inhibition of apoptosis [81,82], promotion of survival [8,75], proliferation [35,83], angiogenesis [10], invasiveness and metastasis [62,84], and is also known to regulate cancer cell metabolism (Fig. 2) [85,86].…”

“…The formation and maintenance of this neovasculature remains always activated as an 'angiogenic switch' and helps tumour development [144]. STAT-3 activation by IL-6 facilitates angiogenesis in many cancers by inducing the expressions of VEGF, bFGF and MMP9 in tumour-associated endothelial cells, TAMs and MDSCs [60,84,143,145]. In addition, the Notch ligand, JAG-2, has been reported to be overexpressed in malignant plasma cells from MM patients, which induces the secretion of IL-6 and VEGF [146], whilst in breast cancer, Notch-3-dependent ERK activation via IL-6 appears to activate JAG-1 (Notch ligand) and CA-IX (a hypoxia survival gene).…”

“…It inhibits growth, besides inducing apoptosis by reducing IL-6 secretion in prostate cancer cell lines, which is suggestive of its use in the treatment of prostate cancer either alone or in combination with chemotherapy [171]. Radiation activates IL-6/STAT-3 signalling, which stimulates tumour invasion and EMT changes and promotes the survival of tumour cells after therapy, thereby conferring resistance to therapy [12,84,156]. However, use of siRNA against IL-6 inhibits tumour regrowth after radiotherapy in prostate cancer and sensitizes tumour cells to radiation by increasing cell death and DNA damage [12].…”

Silencing of type Iγ phosphatidylinositol phosphate kinase suppresses ovarian cancer cell proliferation, migration and invasion

“…Here we further showed that PIPKIγ-deficient SKOV-3 cells indeed exhibited lower mRNA levels of both MMP-2 and MMP-9. Although it has been suggested that the expression of MMP-2 and MMP-9 in ovarian epithelial cells can be regulated by STAT3 (49,50) and PIPKIγ depletion inhibits STAT3 activity similarly in OVCAR-8 cells as in SKOV-3 cells, no significant MMP-2 or MMP-9 reduction was detected in OVCAR-8 cells after PIPKIγ depletion. This suggests some complexity in the regulation of MMP-2 and MMP-9 in different types of epithelial ovarian cancer cells.…”

Niclosamide inhibition of STAT3 synergizes with erlotinib in human colon cancer

“…In the past 5 years, niclosamide has been identified as a potential anticancer agent targeting multiple signaling pathways (eg, NF-κB, ROS, Notch, Wnt/b-catenin, and mTORc1) 18–21. Recently, several studies have reported that niclosamide exhibits antiproliferative activity in head and neck, ovarian, breast, and hematologic cancer 22–25. Till date, no studies demonstrating the therapeutic efficacy of niclosamide in colon cancer are available.…”