Autophagy and tumorigenesis

Department of Pathology, Diller Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
FEBS letters (Impact Factor: 3.17). 04/2010; 584(7):1427-35. DOI: 10.1016/j.febslet.2009.12.034
Source: PubMed


Autophagy, or cellular self-digestion, is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance. Nonetheless, genetic evidence supports that autophagy functions as a tumor suppressor mechanism. Hence, the precise role of autophagy during cancer progression and treatment is both tissue and context dependent. Here, we discuss our current understanding of the biological functions of autophagy during cancer development, overview how autophagy is regulated by cancer-associated signaling pathways, and review how autophagy inhibition is being exploited to improve clinical outcomes.

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    • "More importantly, the best hope for cancer therapeutics may lie in discovering candidate agents targeting core survival/death pathways and even the autophagy-related cancer networks, rather than their individual gene or protein (Turcotte and Giaccia, 2010; Chen et al., 2010). Within this context, further elucidating the complicated survival or death mechanisms and targeting core autophagic pathways would be a promising avenue for discovering potential new anti-neoplastic drug targets from bench to clinic. "
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    • "Paradoxically, in some cases, autophagy can also contribute to autophagic cell death, a form involving cell degradation via the actions of lysosomes (a distinct form of cell death in contrast to type I programmed cell death or apoptosis)9. Although the paradoxical dual effect possible for autophagy in cancer cell fate remains controversial, overwhelming evidence supports the hypothesis that autophagy is an important resistance mechanism to chemotherapy in multiple malignancies101112. "
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    ABSTRACT: Deficiency or mutation in the p53 tumor suppressor gene commonly occurs in human cancer and can contribute to disease progression and chemotherapy resistance. Currently, although the pro-survival or pro-death effect of autophagy remains a controversial issue, increasing data seem to support the idea that autophagy facilitates cancer cell resistance to chemotherapy treatment. Here we report that 5-FU treatment causes aberrant autophagosome accumulation in HCT116 p53(-/-) and HT-29 cancer cells. Specific inhibition of autophagy by 3-MA, CQ or small interfering RNA treatment targeting Atg5 or Beclin 1 can potentiate the re-sensitization of these resistant cancer cells to 5-FU. In further analysis, we show that JNK activation and phosphorylation of Bcl-2 are key determinants in 5-FU-induced autophagy. Inhibition of JNK by the compound SP600125 or JNK siRNA suppressed autophagy and phosphorylation of c-Jun and Bcl-2 but increased 5-FU-induced apoptosis in both HCT116 p53(-/-) and HT29 cells. Taken together, our results suggest that JNK activation confers 5-FU resistance in HCT116 p53(-/-) and HT29 cells by promoting autophagy as a pro-survival effect, likely via inducing Bcl-2 phosphorylation. These results provide a promising strategy to improve the efficacy of 5-FU-based chemotherapy for colorectal cancer patients harboring a p53 gene mutation.
    Scientific Reports 04/2014; 4:4694. DOI:10.1038/srep04694 · 5.58 Impact Factor
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    • "Autophagy is a physiological response to stress and has been suggested to enable cells to adapt and survive and, hence, is considered a pro-survival mechanism [31]. Apoptosis is the best-described form of programmed cell death, but autophagy reportedly contributes to cell death as well. "
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    ABSTRACT: There are a number of dietary components that may prove useful in the prevention and treatment of cancer. In some cultures, fenugreek seeds are used to treat cancer. The current study focuses on the anticancer properties and proteomic profiles of fenugreek seeds, and is prompted by the clinical profile of a case of primary CNS T cell lymphoma that responded to fenugreek treatment and resulted in tumor regression. Various normal and cancer cell lines were exposed to fenugreek extract at differing concentrations (100 mug/ml, 200 mug/ml and 300 mug/ml) and at different time points (0, 24, 48, 72 and 96 hrs). Protein fingerprints of fenugreek grain/seed types, obtained from four different geographical regions, were analyzed by proteomic expression profiles. We observed selective cytotoxic effects of fenugreek extract in vitro to a panel of cancer cell lines, including T-cell lymphoma. Additionally, the cluster analysis of proteomics data showed that the protein profile of the particular fenugreek used by the patient is significantly different from three other regional subtypes of fenugreek extract. The in vitro effect of fenugreek as a substance with significant cytotoxicity to cancer cells points to the potential usefulness of fenugreek in the prevention and treatment of cancer.
    BMC Complementary and Alternative Medicine 03/2014; 14(1):114. DOI:10.1186/1472-6882-14-114 · 2.02 Impact Factor
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