Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells

Abstract

Autophagy, measured as the sequestration of an endogenous cytosolic enzyme (LDH), showed a progressive rate reduction during diethylnitrosamine-induced rat liver carcinogenesis. In primary hepatocellular carcinomas the autophagic activity was only one-fourth of that seen in normal hepatocytes. Reduced autophagy was also observed in peritumorous hepatocytes and in cells from preneoplastic liver, and a complete suppression of autophagic protein degradation was seen in normal hepatocytes treated with ascitic fluid from an ascites hepatoma, suggesting that tumour cells and their precursors may produce autophagy-suppressive factors with an autocrine and paracrine action. In cells from the transplantable rat ascites hepatoma, Yoshida AH-130, autophagic activity was negligible during active (logarithmic) growth, but increased to approximately 0.4%/h at high cell density, i.e. in stationary phase. In contrast to normal hepatocytes, autophagy in the AH-130 cells was not inhibited by ascitic fluid. The hepatoma cells would thus appear to have lost some aspects of autophagy regulation while retaining others. However, even the highest rate of hepatoma cell autophagy was only one-tenth of the maximal activity seen in normal hepatocytes, confirming the hypothesis that reduced autophagy may be an important aspect of growth deregulation in liver cancer.

Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma

“…Autophagy displays a dual conflicting function in cancer cell biology. We have shown that HCC down-regulates autophagic activity (39,40), and recently, autophagy has been proposed as a tumor suppression mechanism, underlying the possibility that activation of autophagy reverses the neoplastic phenotype (25,41). On the contrary, in the present article, inhibition of autophagy enhanced apoptosis, indicating that autophagy contributes to tumor progression as a protective mechanism against stressful conditions (25,42,43).…”

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“…A striking example of how reduced autophagic proteolysis can contribute to cell growth can be found in the development of liver carcinogenesis. This decrease in autophagic flux results from a decrease in the rate of autophagic sequestration and is already detectable in the early preneoplastic stage (Schwarze & Seglen, 1985;Yucel et al, 1989;Kisen et al, 1993). Autophagic flux is then hardly inhibitable by amino acids nor is it inducible by catabolic stimuli (Schwarze & Seglen, 1985;Tessitore et al, 1988;Kisen et al, 1993) and declines in the more advanced stage of cancer development to a rate of less than 20% of that seen in normal hepatocytes (Kisen et al, 1993).…”

“…This decrease in autophagic flux results from a decrease in the rate of autophagic sequestration and is already detectable in the early preneoplastic stage (Schwarze & Seglen, 1985;Yucel et al, 1989;Kisen et al, 1993). Autophagic flux is then hardly inhibitable by amino acids nor is it inducible by catabolic stimuli (Schwarze & Seglen, 1985;Tessitore et al, 1988;Kisen et al, 1993) and declines in the more advanced stage of cancer development to a rate of less than 20% of that seen in normal hepatocytes (Kisen et al, 1993). The fact that the addition of 3-methyladenine to hepatocytes from normal rats increased hepatocyte viability to the same level as observed for the tumour cells (Schwarze & Seglen, 1985) strongly suggests that the fall in autophagic proteolysis contributes to the rapid growth rate of these cells and gives them a selective advantage over the normal hepatocytes.…”

“…It may be that the capacity for autophagy is diminished, but it is also possible that autocrine or paracrine factors, secreted by the tumour cells themselves, continuously suppress macroautophagy (Kisen et al, 1993). Additionally, since amino acids are not able to down-regulate proteolytic rates in tumorigenic cells, one may also speculate that in these cells the components of the S6 signal transduction pathway are under continuous pressure to remain in a highly phosphorylated state.…”

Role of autophagy in the progression and suppression of leukemias

“…As controversial as it sounds, there is evidence that autophagy might have roles in both tumor suppression and tumor progression as extensively reviewed in other papers [3,[53][54][55]. Some studies have shown that the activity of the autophagic pathway decreases in most cancerous cells [56,57], suggesting that autophagy might be a suppressive mechanism for cancer progression. The tumor-suppressive effect of autophagy might be conferred by increased protein degradation and/or by the clearance of damaged organelles from the cytosol.…”