Dietary α-linolenic acid reduces COX-2 expression and induces apoptosis of hepatoma cells

Abstract

Although the mechanisms underlying FAS overexpression in cancer are largely unknown, recent evidence (7-10) strongly suggests that, as in liver, FAS gene transcription in tumor cells is modulated by the sterol regulatory element binding protein-1 (SREBP-1).SREBP-1 is synthesized as an integral protein of the endoplasmic reticulum membranes. As its C-terminal regulatory domain interacts with SREBP cleavage-activating protein (SCAP), the SREBP/SCAP complex migrates to the Golgi membranes, where a two-step cleavage catalyzed by a serine protease [site-1 protease (S1P)] and a metalloprotease [site-2 protease (S2P)] is responsible for the release of the N-terminal sequence of SREBP-1 in the cytoplasm. At the nuclear level, mature SREBP-1, a transcription factor of the basic helix-loop-helix leucine zipper family, activates genes encoding FAS and other lipogenic enzymes by interacting with sterol response elements present in their promoter region (11). Insulin and dietary carbohydrates activate FAS gene transcription by this mechanism, whereas dietary polyunsaturated fatty acids (PUFAs) of both -6 and -3 series negatively modulate FAS expression by depressing SREBP-1 mRNA level and reducing the cleavage of the native protein (12, 13).Recently, it was found that pharmacological inhibitors of FAS are selectively cytotoxic to tumor cells in culture and in vivo (14-17). In particular, the FAS inhibitors cerulenin (2 S ,3 R -epoxy-4-oxo-7 E ,10 E -dodecadienamide) and C75 (3-carboxy-4-octyl-2-methylenebutyrolactone) induce Abbreviations: ACC, acetyl-CoA carboxylase; C/EBP, CCAAT enhancer binding protein; COX-2, cyclooxygenase-2; CPT-1, carnitine palmitoyltransferase-1; FAS, fatty acid synthetase; PPAR ␣ , peroxisome proliferator-activated receptor-␣ ; SCAP, sterol regulatory element binding protein-1 cleavage activating protein; S1P, site-1 protease; S2P, site-2 protease; SREBP-1, sterol regulatory element binding protein-1.

Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer

“…The pro-apoptotic effect of dietary n-3 PUFAs was observed also in vivo using a variety of animal models of cancer, such as rats bearing carcinogen-induced neoplastic and pre-neoplastic lesions in urothelium [151] and colon [152,153], rat tumors transplanted in syngeneic animals including 3924A Morris rat hepatocarcinoma [154,155], or tumors obtained implanting human cells in nude mice, such as human colon adenocarcinoma cells [15], thymoma cells [156], human breast cancer cells [157]. Moreover, increased apoptosis was observed also in normal splenic lymphocytes obtained from Balb/c mice treated with a fish oil diet [158].…”

Eicosapentaenoic Acid Demethylates a Single CpG That Mediates Expression of Tumor Suppressor CCAAT/Enhancer-binding Protein δ in U937 Leukemia Cells

“…In hepatocarcinoma cells, n-3 PUFAs modulate the expression of CCAAT/enhancer-binding protein (C/EBP) transcription factors (18,19). C/EBPs (␣, ␤, ␦, ␥, ⑀, and ) represent a family of master regulators that play an essential role in controlling cell proliferation and differentiation processes of several cell types, including myeloid cells (20).…”

Chemical Profile and Cytotoxic Activity of Leaf Extracts fromSennaspp. from Northeast of Brazil

“…29 Dai et al 30 showed that polyunsaturated fatty acids are cytotoxic to tumor cells, and of the fatty acids tested, linoleic acid (LA) and α-linolenic acid (ALA) were the most effective in suppressing the growth of normal gastric cells ( . The induction of apoptosis by α-linolenic acid (18) (ALA) was observed by Vecchini et al 31 and Scheim 32 and likely occurred because of the reduction of nitric oxide, as proposed by Deshpande et al 33 In recent studies with mouse models, ALA (18) reduced breast tumor growth while increasing the efficacy of chemotherapeutic agents. However, these studies did not confirm whether the effects were caused by ALA or its metabolites.…”