stilbenes and Bile-Duct-Neoplasms

Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells.. The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells.. Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells.. Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD.

Topics: Acetylation; Apoptosis; Autophagy; Autophagy-Related Protein 7; Bile Duct Neoplasms; Cell Line, Tumor; Cholangiocarcinoma; Forkhead Box Protein O1; Humans; Membrane Potential, Mitochondrial; Microtubule-Associated Proteins; Oxidative Stress; Resveratrol; RNA Interference; RNA, Small Interfering; Sequestosome-1 Protein; Stilbenes

After repeated administration of trans-4-acetylaminostilbene to rats, DNA-bound metabolites accumulate to the greatest extent in liver and kidney, which are considered to be nontarget tissues for this carcinogen. To test whether the persistent DNA adducts represent procarcinogenic lesions, an initiation-promotion experiment was carried out using trans-4-acetylaminostilbene as an initiator and phenobarbital, DDT and diethylstilbestrol as promoters. In addition, partial hepatectomy was performed in some groups. Partial hepatectomy alone or in combination with promoters led to the formation of preneoplastic enzyme deficient foci, hyperplastic nodules and hepatoma in great yields. In addition, mammary tumors were observed with diethylstilbestrol promotion. The results support our proposal that aminostilbene derivatives produce procarcinogenic DNA-lesions in many, if not all, tissues and that secondary factors determine when and where tumors arise.

Topics: Adenoma, Bile Duct; Animals; Bile Duct Neoplasms; Body Weight; Carcinogens; DNA; Female; Hyperplasia; Liver; Liver Neoplasms, Experimental; Liver Regeneration; Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Strains; Stilbenes