Basal caspase-3 activity promotes migration, invasion, and vasculogenic mimicry formation of melanoma cells

Abstract

Melanoma is the least common but most serious form of skin cancer. The leading cause of death in melanoma patients is widespread metastasis caused by increased cell motility and a rich blood supply for tumor cells. A unique form of microcirculation called vasculogenic mimicry, which efficiently supplies blood to tumor cells, has been reported recently. Apoptosis-related protein performs a nonapoptotic function to promote migration and invasion of tumor cells. This study focuses on the nonapoptotic role of caspase-3 in melanoma and its effects on the migration, invasion, and vasculogenic mimicry formation of melanoma cells. Human melanoma samples were used to detect active caspase-3 expression and determine its relationship with clinicopathologic parameters. In addition, a human melanoma A375 cell line was used to determine the role of caspase-3 in migration and invasion using z-DEVD-fmk, a selective caspase-3 inhibitor, to inhibit caspase-3 activity. The findings suggest that active caspase-3 is expressed in nonapoptotic melanoma cells and is related to metastasis and vasculogenic mimicry formation in patients with melanoma. Low doses of caspase-3 inhibitor reduced caspase-3 activity without affecting cell apoptosis. Inhibition of caspase-3 activity using low-dose z-DEVD-fmk decreased the migration, invasion, and vasculogenic mimicry formation of melanoma cells in vitro. Similarly, downregulation of caspase-3 by specific small interfering RNA also inhibited the migratory, invasive, and tube-forming potential of melanoma cells. The caspase-3-mediated promotion of melanoma cell motility may be because of the cleavage of matrix metalloproteinase-2.

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Increased caspase 3 expression is found in OSCC compared with normal oral epithelium 76. These findings question the apoptotic role of caspase 3, suggesting its nonapoptotic functions in oral cancers, as implicated in other cancers 77, 78, 79.…”

CD271 Down-Regulation Promotes Melanoma Progression and Invasion in Three-Dimensional Models and in Zebrafish

“…Indeed, survivin and Notch1, involved in M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 melanoma progression, are more expressed in SKMEL28, WM793-B and 1205Lu cells than in less aggressive cell lines. In addition, active caspase-3, which promotes migration and invasion of non apoptotic melanoma cells (Liu et al, 2013), is higher in SKMEL28 and 1205Lu than in the other spheroids. HIF-1α is higher in spheroids derived from advanced stage melanomas (WM266-4 and 1205Lu) ( Figure 1I).…”

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

“…Thus, it might be counterintuitive that high levels of apoptosis are linked to poor prognosis in cancer (Jalalinadoushan et al, 2004;Leoncini et al, 1993;Nakopoulou et al, 2001;Naresh et al, 2001;Ohbu et al, 1995;Sun et al, 2006). The mechanism behind this unexpected observation is only now beginning to be understood: it has been shown that apoptotic signaling can drive tumor proliferation and invasion in different tumor models (Ballesteros-Arias et al, 2014;Gdynia et al, 2007;Liu et al, 2013;Maeda et al, 2005;Rudrapatna et al, 2013). Likewise, the treatment of tumors by chemotherapy or radiotherapy has recently been shown to induce tumor repopulation by increasing the release of PGE2 by apoptotic cells, which stimulates the growth of surviving tumor cells (Huang et al, 2011;Kurtova et al, 2014).…”