Search

The anti-tumoral activity of somatostatin has been demonstrated in both animal experiments and human tumors. Clinical trials have reported conflicting results. We therefore hypothesized that somatostatin might have different effects in various hepatocellular carcinoma cells. Their clarification would possibly allow for the better selection of patients suitable for the optimal treatment results. We studied the mRNA and protein expression of TNF receptors and the TNFa-induced apoptosis using the HepG2 and the Hep3B human hepatocellular carcinoma cells after incubation with the somatostatin analog octreotide. RT-PCR, Western blot, and parameters associated with apoptosis (NF-kB nuclear translocation, P65 Ser536 and P65 Ser468 phosphorylation, DNA fragmentation) were assessed. Only TNFR1 was constitutively present in the two cell lines. Octreotide incubation led to an earlier reduction in TNFR1 mRNA and protein in HepG2 compared to Hep3B cells (1 h and 6–12 h, respectively). NF-kB translocation to the nucleus was induced by TNFa and was more prominent in Hep3B. Translocation was unaffected by octreotide. Serine phosphorylation was significantly induced by TNFa and was more evident in the Hep3B cells. TNFa-induced Ser536 phosphorylation was inhibited by octreotide only in the HepG2 cells. DNA fragmentation was not influenced by either octreotide or TNFa in the HepG2 cells, but TNFa induced fragmentation in the Hep3B cells (1.8-fold increase) verified by the TUNEL index (43 compared to 19 for the HepG2 cells). Octreotide and TNFa co-incubation induced apoptosis in the HepG2 cells (1.7-fold increase compared to controls) but inhibited apoptosis in the Hep3B cells. We conclude that: (1) octreotide reduced TNFR1 receptor expression in both cell lines, (2) parameters of apoptosis were differentially affected by octreotide in the two cell lines, and (3) this might be a partial explanation for the conflicting results of somatostatin analog treatment in human hepatocellular carcinoma trials.

The pathogenesis of inflammatory bowel disease (IBD) implicates several interconnecting factors. Immunity and external factors interact, and most aspects are still under investigation. Autophagy and apoptosis are two critical pathways that decide the fate of the individual cells of the intestinal mucosa. Experimental and clinical data indicate that the two are closely interconnected and usually mutually exclusive. However, despite the abundant information on their role, very limited translation into therapeutic application has been seen during recent years. In this review, research on these two pathways is presented. After a general overview of autophagy and apoptosis, their association with IBD, including the important mitophagy and ferroptosis, is discussed. The influence of autophagy- and apoptosis-related genes is also discussed. Finally, the interplay of autophagy and apoptosis in IBD is presented and the implications for treatment applications are examined. It is shown that dysregulated autophagy leads to increased apoptosis of enterocytes and impairs the tight junction proteins of the protective intestinal barrier. Dysregulated autophagy also induces the downregulation of lysozyme and the other antimicrobial proteins’ production. Mucus production by the goblet cells is also reduced due to defective autophagy and increased apoptosis.

The pathogenesis of primary biliary cholangitis (PBC) is particularly complicated as both intrinsic and extrinsic factors are implicated. Several forms of cellular death, both programmable and non-programmable, operate leading biliary epithelial cells (BECs) to elimination. The precise role of critical pathways like autophagy, apoptosis, senescence, and their interplay has not been fully clarified. Therefore, in this review, data on these important mechanisms are presented and their implication in PBC is discussed. The interplay of the three mechanisms is examined and the factors that drive them are analyzed. Moreover, the upstream drivers of autophagy, apoptosis, and senescence are presented. They include the loss of the protective bicarbonate umbrella in BECs due to the reduction of activity of the anion exchanger 2 (AE2) with the resultant activation of the intracellular soluble adenylyl cyclase (sAC). The role of toxic bile acids is also presented. A sequence of events is proposed including involvement of the gut-liver axis and the possible role of ferroptosis. Finally, a brief account of the initial trigger of the disease is given.

The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.