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15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of cyclooxygenase-2-catalized arachidonic acid metabolism, has been shown to stimulate breast cancer cell proliferation and migration through Akt activation, but the underlying mechanisms remain poorly understood. In the present study, we investigated the effects of 15d-PGJ2 on the activity of PTEN, the inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt axis, in human breast cancer (MCF-7) cells. Since the α,β-unsaturated carbonyl moiety in the cyclopentenone ring of 15d-PGJ2 is electrophilic, we hypothesized that 15d-PGJ2-induced Akt phosphorylation might result from the covalent modification and subsequent inactivation of PTEN that has several critical cysteine residues. When treated to MCF-7 cells, 15d-PGJ2 bound to PTEN, and this was abolished in the presence of the thiol-reducing agent dithiothreitol. A mass spectrometric analysis by using recombinant and endogenous PTEN protein revealed that the cysteine 136 residue (Cys136) of PTEN is covalently modified upon treatment with 15d-PGJ2. Notably, the ability of 15d-PGJ2 to covalently bind to PTEN as well as to induce Akt phosphorylation was abolished in the cells expressing a mutant form of PTEN in which Cys136 was replaced by serine (C136S-PTEN). The present study demonstrates for the first time that electrophilic 15d-PGJ2 directly binds to cysteine 136 of PTEN and provides new insight into PTEN loss in cancer progression associated with chronic inflammation. These observations suggest that 15d-PGJ2 can undergo nucleophilic addition to PTEN, presumably at Cys136, thereby inactivating this tumor suppressor protein with concomitant Akt activation. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs produce a variety of cytokines, growth factors and extracellular matrix proteins, thereby stimulating tumor progression. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through cross-talk with them. Resveratrol ( trans -3,4′5,-trihydroxystilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the effects of resveratrol on CAF-induced migration, invasion and self-renewal activity of breast cancer cells. Resveratrol inhibited proliferation, migration and invasion of human breast cancer cells treated with CAF-conditioned media (CAF-CM). Resveratrol treatment suppressed the CAF-CM-induced expression of Cyclin D1, c-Myc, MMP-2 and MMP-9. In addition, resveratrol inhibited Sox2 expression as well as activation of Akt and STAT3 induced by CAF-CM in breast cancer cells. Further, resveratrol abrogated stemness properties and reduced the expression of self-renewal signaling molecules in stem-like breast cancer cells. Taken together, the present study provides insights into the role of resveratrol in tumor microenvironment with focus on interaction between cancer cells and the hosting niche. [ABSTRACT FROM AUTHOR]

The tumor suppressor phosphatase and tensin homologue (PTEN) has phosphatase activity, with phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase (PI3K), as one of the principal substrates. PTEN is a negative regulator of the Akt pathway, which plays a fundamental role in controlling cell growth, survival, and proliferation. Loss of PTEN function has been observed in many different types of cancer. Functional inactivation of PTEN as a consequence of germ-line mutations or promoter hypermethylation predisposes individuals to malignancies. PTEN undergoes posttranslational modifications, such as oxidation, acetylation, phosphorylation, SUMOylation, and ubiquitination, which influence its catalytic activity, interactions with other proteins, and subcellular localization. Cellular redox status is crucial for posttranslational modification of PTEN and its functional consequences. Oxidative stress and inflammation are major causes of loss of PTEN function. Pharmacologic or nutritional restoration of PTEN function is considered a reliable strategy in the management of PTEN-defective cancer. In this review, we highlight natural compounds, such as curcumin, indol-3 carbinol, and omega-3 fatty acids, that have the potential to restore or potentiate PTEN expression/activity, thereby suppressing cancer cell proliferation, survival, and resistance to chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

SIRT1, an NAD+-dependent histone/protein deacetylase, has diverse physiological actions. Recent studies have demonstrated that SIRT1 is overexpressed in colorectal cancer, suggesting its oncogenic potential. However, the molecular mechanisms by which overexpressed SIRT1 induces the progression of colorectal cancer and its inhibition remain largely unknown. Curcumin (diferuloymethane), a major component of the spice turmeric derived from the plant Curcuma longa L., has been reported to exert chemopreventive and anti-carcinogenic effects on colon carcinogenesis. In the present study, we found that curcumin reduced the expression of SIRT1 protein without influencing its mRNA expression in human colon cancer cells, suggesting posttranslational regulation of SIRT1 by this phytochemical. Notably, ubiquitination and subsequent proteasomal degradation of SIRT1 were induced by curcumin treatment. Results of nano-LC-ESI-MS/MS revealed the direct binding of curcumin to cysteine 67 of SIRT1. In line with this result, the protein stability and clonogenicity of a mutant SIRT1 in which cysteine 67 was substituted by alanine were unaffected by curcumin. Taken together, these observations suggest that curcumin facilitates the proteasomal degradation of oncogenic SIRT1 through covalent modification of SIRT1 at the cysteine 67 residue. [ABSTRACT FROM AUTHOR]

Nuclear factor E2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of a battery of genes encoding antioxidant and carcinogen detoxifying enzymes. In contrast to its tumor suppressive functions in normal cells, Nrf2 facilitates tumor growth and progression through metabolic reprograming in some cancer cells. Our previous study has demonstrated that 15-deoxy-Δ12,14-prostaglandin J2 and 4-hydroxyestradiol induce overactivation of Nrf2 and consequently overexpression of its target protein, heme oxygenase-1 (HO-1), in human breast cancer cells. More recently, we have demonstrated the involvement of Nrf2 in experimentally induced hepatocarcinogenesis (N.H.K. Chi et al., Cancer Res., 2017). In this context, the cellular stress response or cytoprotective signaling mediated via the Nrf2-HO-1 axis is hijacked by cancer cells. This may facilitate the remodeling of the tumor microenvironment making it advantageous for the autonomic growth of cancer cells, metastasis, angiogenesis, tolerance to anticancer therapy, and self-renewal activity of stem-like cells. [ABSTRACT FROM AUTHOR]

15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2), a representative J-series cyclopentenone prostaglandin, has biphasic roles in cell proliferation and apoptosis. Hypoxia inducible factor-1 (HIF-1) regulates expression of various genes involved in tumor growth and angiogenesis. In the present study, treatment of human breast cancer (MCF-7) cells with 15d-PGJ2resulted in the accumulation of the α-subunit of HIF-1. Pretreatment with zinc protoporphyrin IX, a pharmacological inhibitor of heme oxygenase-1 (HO-1), as well as siRNA knockdown ofHO-1gene in MCF-7 cells attenuated 15d-PGJ2-mediated HIF-1α accumulation. 15d-PGJ2treatment increased intracellular production of reactive oxygen species (ROS), which was mediated by HO-1 induction. Preincubation of MCF-7 cells with trolox, a water-soluble form of vitamin E, attenuated 15d-PGJ2-induced HIF-1α expression although HO-1 expression was unchanged. This finding suggests that ROS accumulated as a consequence of HO-1 up-regulation can enhance HIF-1α expression in MCF-7 cells treated with 15d-PGJ2. Alternatively, 15d-PGJ2was found to covalently bind to HIF-1α prolyl-4-hydroxylase 2 (PHD2) in MCF-7 cells, which hampers the proline hydroxylation of HIF-1α, thereby disrupting ubiquitin-dependent proteasomal degradation of this transcription factor. Pretreatment with thiol reducing agents blunted 15d-PGJ2-induced HIF-1α stabilization, indicative of a cysteine residue as a direct target of 15d-PGJ2. Molecular docking analysis suggests that 15d-PGJ2preferentially binds to PHD2 in the vicinity of the Cys201residue based on binding energies and carbon–sulfur distances. In summary, 15d-PGJ2stabilizes HIF-1α in MCF-7 cells through HO-1 induction with subsequent ROS generation and also through direct modification of PHD2. [ABSTRACT FROM AUTHOR]