Autophagy involvement in oncogenesis

Abstract

Various clinical and experimental findings have revealed the causal relationship between autophagy failure and oncogenesis, and several mechanisms have been suggested to explain this relationship. We recently proposed two additional mechanisms: centrosome number dysregulation and the failure of autophagic cell death. Here, we detail the mechanical relationship between autophagy failure and oncogenesis.

Keywords: alternative autophagy; autophagic cell death; autophagy; centrosome; oncogenesis.

FIGURE 1

Hypothetical model of autophagy. There are at least two modes of autophagy, namely, canonical and alternative autophagy. Canonical autophagy requires autophagy‐related protein (Atg)‐5 and originates from the endoplasmic reticulum (ER) membrane. In contrast, alternative autophagy occurs independently of Atg5 and originates from the Golgi membrane. LC3, microtubule‐associated protein 1A/1B‐light chain 3; PI3K, phosphatidylinositol 3‐kinase; Rab9, Ras‐related protein 9; Ulk1, Unc51‐like kinase 1

FIGURE 2

Mechanism of genotoxic stress‐induced autophagy (modified from ref. ¹⁴ ). (A) Genotoxic stress‐induced alternative autophagy is activated by phosphorylated Unc51‐like kinase 1 (p‐Ulk1)⁷⁴⁶, which is entirely localized on the Golgi membrane. The indicated mouse embryonic fibroblasts were treated with etoposide and immunostained with anti‐p‐Ulk1⁷⁴⁶ and anti‐GS28 antibodies. Representative images of p‐Ulk1⁷⁴⁶ (upper panels) and merged images (lower panels) are shown. Arrowheads indicate p‐Ulk1⁷⁴⁶ signals on the Golgi. (B) Schematic model of genotoxic stress‐induced autophagy. Genotoxic stress induces Ulk1 dephosphorylation at serine⁶³⁷ in a p53/protein phosphatase magnesium‐dependent 1D, delta isoform (PPM1D)‐dependent manner. This step is essential for both autophagy types. The subsequent phosphorylation of Ulk1 at serine⁷⁴⁶ by p53/RIPK3 is essential for the induction of alternative autophagy

FIGURE 3

Mechanism of oncogenesis from an excess number of centrosomes. During prophase, two centrosomes move to opposite poles of the cell to properly segregate chromosomes. Excess centrosomes cause chromosome mis‐segregation, leading to genomic instability that may trigger oncogenesis

FIGURE 4

Autophagy regulates centrosome number (modified from ref. ¹⁵ ). (A) Autophagy‐related protein 5 (Atg5)‐deficient cells contain excess centrosomes. Centrosomes were immunostained with an anti‐γ‐tubulin antibody. Arrows indicate cells with excess centrosomes. (B) Atg5‐deficient cells contain many aberrant centrosomal protein 63 (Cep63) puncta. Atg5^−/− mouse embryonic fibroblasts were immunostained with anti‐γ‐tubulin antibody (green; left) and anti‐Cep63 antibody (red; right) and were examined by fluorescence microscopy. Arrows and arrowheads indicate mature centrosomes and extra Cep63 dots, respectively. (C) Schematic model of autophagy failure‐induced centrosome overproduction. In healthy cells, the centrosome number remains normal (n = 2) because cytosolic Cep63 dots are degraded into autophagosomes via p62. In autophagy‐deficient cells, the centrosome number increases because many Cep63 dots exist in the cytosol

FIGURE 5

Involvement of Jun amino‐terminal kinase (JNK) in autophagic cell death. (A) Representative electron micrograph of autophagic cell death. Mouse embryonic fibroblasts (MEFs) were treated with etoposide for 24 h. There are many autophagic vacuoles (arrows) present in the cytosol, and the organelles are almost normal. (from ref. ⁵ ). (B) Reduction of etoposide‐induced death by the inhibition of JNK. MEFs were treated with etoposide in the presence of JNK inhibitor SP600125 for 24 h, and then examined by phase‐contrast microscopy (modified from ref. ³⁷ )