Curcumin inhibits protein phosphatases 2A and 5, leading to activation of mitogen-activated protein kinases and death in tumor cells

Abstract

Curcumin can induce p53-independent apoptosis. However, the underlying mechanism remains to be defined. Here, we show that curcumin-induced apoptosis in a panel of tumor cells with mutant p53. Curcumin rapidly induced activation of the mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2 (Erk1/2) and c-Jun N-terminal kinase (JNK). Inhibition of JNK (with SP600125) or Erk1/2 (with U0126) partially prevented curcumin-induced cell death in the cells. Similarly, expression of dominant negative c-Jun or downregulation of Erk1/2 in part attenuated curcumin-induced cell death. It appears that curcumin-induced activation of MAPKs and apoptosis was due to induction of reactive oxygen species (ROS), as pretreatment with N-acetyl-L-cysteine, a ROS scavenger, blocked these events. Furthermore, we found that curcumin-induced activation of MAPK pathways was related to inhibition of the serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5). Overexpression of PP2A or PP5 partially prevented curcumin-induced activation of JNK and Erk1/2 phosphorylation as well as cell death. The results suggest that curcumin induction of ROS activates MAPKs, at least partially by inhibiting PP2A and PP5, thereby leading to p53-independent apoptosis in tumor cells.

Curcuma Longa (Curcumin) Decreases In Vivo Cisplatin-Induced Ototoxicity Through Heme Oxygenase-1 Induction

“…The mechanisms by which curcumin mediates its effects remain unclear. Several studies have demonstrated that curcumin acts as a free radical scavenger conferring cytoprotective effects; other research groups have remarked its prooxidant activity in tumor cells, favoring ROS generation and apoptosis (38,40). Further studies may contribute to elucidate the pro-oxidant and proapoptotic effects of curcumin at different doses in cancer cells and in the cochlea.…”

Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells

“…Accumulating data have shown that the phosphatase activity of PP2Ac is modulated by its association with PP2A-A, -B regulatory subunits [42]. Also the activity can be turned ''on'' and ''off'' by posttranslational modification such as phosphorylation and carboxyl methylation of PP2Ac [58,59]. Multiple studies have described that disturbances in the expression and/or function of PP2A are linked to autoimmune diseases [27,30,31].…”

c-Myc modulation: a key role in melanoma drug response

“…At the same way, PP2A inhibitors have been reported as potential anti-cancer agents. 35 However, their potentiality in melanoma treatment has not been tested, yet.…”