Roles of JNK‐1 and p38 in selective induction of apoptosis by capsaicin in ras‐transformed human breast epithelial cells

Abstract

Efforts have been made to develop a chemoprevention strategy that selectively triggers apoptosis in malignant cancer cells. Previous studies showed that capsaicin, the major pungent ingredient of red pepper, had differential effect between normal and transformed cells. As an approach to unveil the molecular mechanism by which capsaicin selectively induces apoptosis in transformed cells, we investigated the effect of capsaicin in nontransformed and ras-transformed cells of a common origin: parental (MCF10A) and H-ras-transformed (H-ras MCF10A) human breast epithelial cells. Here, we show that capsaicin selectively induces apoptosis in H-ras-transformed cells but not in their normal cell counterparts. The capsaicin-induced apoptosis, which is dependent on ras transformation, involves the activity of DEV- Dase (caspase-3 like). In H-ras MCF10A cells, capsaicin treatment markedly activated c-Jun N-terminal protein kinase (JNK)-1 and p38 matigen-activated protein kinase (MAPK) while it deactivated extracellular signal-regulated protein kinases (ERKs). The use of kinase inhibitors and overexpression of dominant-negative forms of MAPKs demonstrated a role of JNK-1 and p38, but not that of ERKs, in apoptosis inducedby capsaicin in H-ras-transformed MCF10A cells. Based on the present study, we propose that capsaicin selectively induces apoptosis through modulation of ras-downstream signaling molecules in ras-activated MCF10A cells. Taken in conjunction with the fact that uncontrolled ras activation is probably the most common genetic defect in human cancer cells, our finding may be critical to the chemopreventive potential of capsaicin and for developing a strategy to induce tumor cell-specific apoptosis.

Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6–Inducible STAT3 Activation

“…In culture, capsaicin has been found to selectively suppress the growth of various human tumor cells (14,15), including leukemic (16 -18), gastric (19), hepatic (20), glioma (21), and prostate cells (9). How capsaicin mediates its anticancer effects is not fully understood, but the roles of NADH oxidase activity (14), proteasome (9), cyclooxygenases (22), c-Jun NH 2 -terminal kinase (23), nuclear factor-nB (24), peroxisome proliferator-activated receptor g (25,26), peroxynitrite (21), and mitochondrial respiration (27) have been implicated. Its immunosuppressive effects have been linked to its ability to suppress nuclear factor-nB activation (28).…”

Genipin, a constituent of Gardenia jasminoides Ellis, induces apoptosis and inhibits invasion in MDA-MB-231 breast cancer cells

“…Metastasis, a characteristic of highly malignant cancers with poor clinical outcome, is one of the major causes of mortality in breast cancer patients. Therefore, anti-tumor agents that may inhibit invasion and migration of breast cancer cells have been extensively pursued in many laboratories, including ours (35,36). Although many studies have reported the anti-tumor activity of genipin in various cancer cells, there is a limited amount of information on the anti-invasive activity of genipin.…”

Distinct thymocyte subsets express the vanilloid receptor VR1 that mediates capsaicin-induced apoptotic cell death

“…Increase in procaspase-3 cleavage was observed during CPS-induced apoptosis of human hepatocarcinoma cells, 34 and increased caspase-3 activity occurred in the CPS-induced apoptosis of H-Ras-transformed breast epithelial cells. 55 Moreover, the caspase-3 inhibitor (Ac-DEVD-cmk) blocked DNA fragmentation in Jurkat cells exposed to vanilloid phorbol 12-phenylacetate 13 acetate 20-homovanillate.…”