Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer

Abstract

Abstract. Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-X L and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidylinositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumininduced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspasedependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

Superoxide anion and proteasomal dysfunction contribute to curcumin-induced paraptosis of malignant breast cancer cells

“…In our study, curcumin demonstrated preferential cytotoxicity to malignant breast cancer cells over normal breast cells. Consistent with our results, curcumin has demonstrated selective killing of various cancer cell types while sparing normal cells [3][4][5]. However, the mechanism underlying the selective cytotoxicity of curcumin against cancer is not yet well understood.…”

“…Clinical trials have revealed that curcumin may produce antitumor effects in individuals with precancerous lesions or those who are at a high risk for developing cancer [3]. Furthermore, curcumin has demonstrated selective killing of various cancer cell types, while sparing normal cells [3][4][5]. Such observations suggest that curcumin is a pharmacologically safe agent that may be used not only in cancer chemoprevention, but also in cancer therapy, either as a primary therapeutic agent or as an adjuvant to traditional chemotherapy.…”

Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells

“…Curcumin (diferuloylmethane) is a major constituent of turmeric powder, which is extracted from the rhizomes of the plant curcuma longa. Many pharmacological and clinical studies support the fact that curcumin has chemopreventive and antiproliferative activity against a variety of human cancers including pancreatic cancers (Ammon and Wahl, 1991;Li et al, 2004;Lev-Ari et al, 2006;Mitra et al, 2006;Reddy et al, 2006;Wang et al, 2006;Aggarwal et al, 2007;Bachmeier et al, 2007;Hauser et al, 2007;Shankar and Srivastava, 2007;Wahl et al, 2007). In addition, curcumin is also pharmacologically safe as it is a naturally occurring compound used as a food-colouring agent and in traditional medicines to treat various diseases in Asian countries (Ammon and Wahl, 1991;Goel et al, 2008).…”

“…Inhibition of cell growth and induction of apoptosis is the common mechanism by which curcumin shows its anticancer effects. Accumulating evidence suggests the involvement of multiple-signaling pathways by which curcumin causes growth suppression of human cancer cells (Cheng et al, 2001;Hidaka et al, 2002;Bharti et al, 2003;Kim et al, 2003;Shishodia et al, 2003;Blasius et al, 2006;Lev-Ari et al, 2006;Mitra et al, 2006;Park et al, 2006;Tan et al, 2006;Aggarwal et al, 2007;Aoki et al, 2007;Deeb et al, 2007;Fahey et al, 2007;Lin et al, 2007Lin et al, , 2008Marín et al, 2007;Shankar and Srivastava, 2007;Srivastava et al, 2007;Weir et al, 2007;Binion et al, 2008;Freudlsperger et al, 2008;Ji et al, 2008;Kasinski et al, 2008;Mackenzie et al, 2008;Shankar et al, 2008;Sun et al, 2008). Phase I clinical trials of curcumin demonstrated encouraging chemopreventive effects in patients with high-risk or pre-malignant lesions.…”

Mechanisms of apoptosis resistance and treatment strategies to overcome them in hormone‐refractory prostate cancer

“…Shankar and Srivastava reported that curcumin, a major chemical component of turmeric, down-regulated the expression of Bcl-2 and Bcl-X L and up-regulated the expression of Bax and Bak in prostate cancer cells. 57 Thus, concomitant treatment with mTOR inhibitors and curcumin may provide promising therapeutic possibilities 16 The synergistic increase in apoptosis was associated with an increase in p21 activity, which was associated with downstream amplification of the caspase cascade. Another study on TRAIL-mediated apoptosis in HRPC evaluated the combined effects of TRAIL and doxorubicin in inducing apoptosis in prostate cancer cell lines.…”