Upregulation of tissue inhibitor of matrix metalloproteinases-1 confers the anti-invasive action of cisplatin on human cancer cells

Abstract

Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the antiinvasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time-and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.

Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion

“…Consistent with the report of Ramer et al (21), treatment of HeLa cells not expressing Cx32 with SB203580 or PD98059 did not affect adhesion and migration (data not shown). Both SB203580 and PD98059 had no impact on the growth of wild-type HeLa cells as assessed by SRB (data not shown), suggesting that the effects of these inhibitors on adhesion and migration are unrelated to cell growth.…”

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1

“…4A,B, Table 2). As previously described, SB203580 and PD98059 alone did not modulate baseline TIMP-1 expression and Matrigel invasion of HeLa cells [29].…”

“…With reference to a number of data reporting an anti-invasive effect of TIMP-1 on cancer cell invasion [23,[25][26][27][28][29][30][31], the present work focussed on the causal link of cannabinoid receptor- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 An invasion-associated effect that is mainly determined by the ability of cancer cells to secrete matrix-degrading enzymes or to modulate their activity rather than on cellular motility was substantiated by the finding that reduced Matrigel invasion was not associated with a decrease of transmigration through uncoated Boyden chambers after cannabidiol treatment.…”

“…[24]). Among the four distinct members of the TIMP family, elevated TIMP-1 was shown to mediate the anti-invasive effects of several anticarcinogenic drugs [23,[25][26][27][28][29]. Furthermore, decreased TIMP-1 levels were demonstrated to correlate with high cancer invasiveness [30,31].…”

Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

“…Whereas ERK predominantly confers survival advantage to cells during most stress conditions in various types of cells, p38 is associated with cell death [9]. Several signalling transduction pathways activated by cisplatin, such as the MAPK pathway components, have been correlated to matrix metalloproteinases (MMPs) activation and expression [10]; furthermore, the anti-invasive properties of cisplatin associated with decrease in MMPs activity have also been reported [11]. Stimulation of MMPs production in some cancer cells appeared to be EGFR-dependent [12], whilst, on the other hand, among multiple mechanisms for EGFR transactivation, the autocrine/paracrine release of soluble EGF A c c e p t e d M a n u s c r i p t…”