Curcumin Triggers p16-Dependent Senescence in Active Breast Cancer-Associated Fibroblasts and Suppresses Their Paracrine Procarcinogenic Effects

Abstract

Activated cancer-associated fibroblasts (CAFs) or myofibroblasts not only facilitate tumor growth and spread but also affect tumor response to therapeutic agents. Therefore, it became clear that efficient therapeutic regimens should also take into account the presence of these supportive cells and inhibit their paracrine effects. To this end, we tested the effect of low concentrations of curcumin, a pharmacologically safe natural product, on patient-derived primary breast CAF cells. We have shown that curcumin treatment upregulates p16(INK4A) and other tumor suppressor proteins while inactivates the JAK2/STAT3 pathway. This reduced the level of alpha-smooth muscle actin (α-SMA) and the migration/invasion abilities of these cells. Furthermore, curcumin suppressed the expression/secretion of stromal cell-derived factor-1 (SDF-1), interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), MMP-9, and transforming growth factor-β, which impeded their paracrine procarcinogenic potential. Intriguingly, these effects were sustained even after curcumin withdrawal and cell splitting. Therefore, using different markers of senescence [senescence-associated β-galactosidase (SA-β-gal) activity, Ki-67 and Lamin B1 levels, and bromodeoxyuridine incorporation], we have shown that curcumin markedly suppresses Lamin B1 and triggers DNA damage-independent senescence in proliferating but not quiescent breast stromal fibroblasts. Importantly, this curcumin-related senescence was p16(INK4A)-dependent and occurred with no associated inflammatory secretory phenotype. These results indicate the possible inactivation of cancer-associated myofibroblasts and present the first indication that curcumin can trigger DNA damage-independent and safe senescence in stromal fibroblasts.

Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets

“…Several studies have shown that curcumin is involved in cell cycle control via upregulation of P16 [61,62]. P16 induced cellular senescence by curcumin has been reported in breast cancer associated fibroblasts [63,64]. In the present study, increased levels of P16 were observed up to 24 hours in MCF 10A cells co-treated with PhIP and curcumin as compared to cells that were treated only with PhIP.…”

Attenuation of hind-limb suspension-induced bone loss by curcumin is associated with reduced oxidative stress and increased vitamin D receptor expression

“…Even though there is little information about the negative effects of curcumin provided in diet, in vitro curcumin can induce apoptosis of both normal and cancer cells [39]. At high concentration, curcumin induced detrimental effects, including cell senescence, even cell death, which was found in cancer MCF7, HCT116, and U2OS cells [40] and cancer-associated fibroblasts [41]. It is not difficult to imagine that acceleration of senescence of normal cells could be detrimental.…”

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…This line of treatment is attractive in many aspects: Curcumin is a pharmacologically safe natural product; it is active at low doses; its effects are maintained even after drug withdrawal and cell propagation; it triggers DNA damage-independent senescence only in proliferating cells (including CAFs), thus sparing healthy cells; and, last, the p16 INK4A -dependent senescence that it triggers is not accompanied by an inflammatory secretory phenotype (Hendrayani et al 2013). …”