Curcumin-Induced Apoptosis in Scleroderma Lung Fibroblasts

Abstract

Scleroderma, a disease involving excessive collagen deposition, can be studied using fibroblasts cultured from affected tissues. We find that curcumin, the active component of the spice turmeric, causes apoptosis in scleroderma lung fibroblasts (SLF), but not in normal lung fibroblasts (NLF). This effect is likely to be linked to the fact that although curcumin induces the expression of the phase 2 detoxification enzymes heme oxygenase 1 and glutathione S-transferase P1 (GST P1) in NLF, SLF are deficient in these enzymes, particularly after curcumin treatment. The sensitivity of cells to curcumin-induced apoptosis and the expression of GST P1 (but not heme oxygenase 1) are regulated by the epsilon isoform of protein kinase C (PKCepsilon). SLF, which contain less PKCepsilon and less GST P1 than NLF, become less sensitive to curcumin-induced apoptosis and express higher levels of GST P1 when transfected with wild-type PKCepsilon, but not with dominant-negative PKCepsilon. Conversely, NLF become sensitive to curcumin-induced apoptosis and express lower levels of GST P1 when PKCepsilon expression or function is inhibited. The subcellular distribution of PKCepsilon also differs in NLF and SLF. PKCepsilon is predominantly nuclear or perinuclear in NLF but is associated with stress fibers in SLF. Just as PKCepsilon levels are lower in SLF than in NLF in vitro, PKCepsilon expression is decreased in fibrotic lung tissue in vivo. In summary, our results suggest that a signaling pathway involving PKCepsilon and phase 2 detoxification enzymes provides protection against curcumin-induced apoptosis in NLF and is defective in SLF. These observations suggest that curcumin may have therapeutic value in treating scleroderma, just as it has already been shown to protect rats from lung fibrosis induced by a variety of agents.

Self-Assembled Dextrin Nanogel as Curcumin Delivery System

“…The ability of curcumin to induce apoptosis in cancer cells, without cytotoxic effects on the healthy ones, is suggestive of a relevant anti-cancer potential. For instance, curcumin leads to apoptosis in scleroderma lung fibroblasts without affecting normal lung fibroblasts [3]. Preferential uptake of curcumin by tumor cells compared to normal cells was also demonstrated.…”

Opposing Effects of Protein Kinase Cα and Protein Kinase Cϵ on Collagen Expression by Human Lung Fibroblasts Are Mediated via MEK/ERK and Caveolin-1 Signaling

“…Depleting PKC⑀ in normal lung fibroblasts (NLF) inhibits expression of the extracellular matrix protein tenascin-C, whereas depleting PKC⑀ in SLF promotes tenascin-C expression (11). SLF are deficient in PKC⑀ and are sensitive to curcumin-induced apoptosis, whereas NLF are insensitive to curcumin (12). The importance of PKC⑀ in regulating the sensitivity of cells to curcumin is demonstrated by the observations that 1) increasing PKC⑀ expression in SLF provides protection against curcumin and 2) decreasing PKC⑀ expression or activity in NLF causes the cells to become sensitive to curcumin (12).…”

Signaling pathways regulating intercellular adhesion molecule 1 expression by endothelin 1: Comparison with interleukin‐1β in normal and scleroderma dermal fibroblasts

“…The ratio of expression of these 2 isoforms differs substantially in scleroderma dermal fibroblasts, with greater PKC␦ expression (Figure 6D). Reduced expression of PKC in scleroderma lung fibroblasts has been reported previously (34,35). .…”