Two Faces of Autophagy in the Struggle against Cancer

Abstract

Autophagy can play a double role in cancerogenesis: it can either inhibit further development of the disease or protect cells, causing stimulation of tumour growth. This phenomenon is called "autophagy paradox", and is characterised by the features that the autophagy process provides the necessary substrates for biosynthesis to meet the cell's energy needs, and that the over-programmed activity of this process can lead to cell death through apoptosis. The fight against cancer is a difficult process due to high levels of resistance to chemotherapy and radiotherapy. More and more research is indicating that autophagy may play a very important role in the development of resistance by protecting cancer cells, which is why autophagy in cancer therapy can act as a "double-edged sword". This paper attempts to analyse the influence of autophagy and cancer stem cells on tumour development, and to compare new therapeutic strategies based on the modulation of these processes.

Keywords: anticancer therapies; apoptosis; autophagy modulation; cancer stem cells; cell death.

Figure 1

Stages of apoptosis. (A) The first morphological symptom of apoptosis is a change at the nucleus level. (B) Chromatin undergoes condensation and aggregates under the nuclear membrane, then the nucleus shrinks and undergoes fragmentation. (C) Next stage of “dying” is cytoplasm condensation and creation of characteristic bubbles on the cell surface. (D) Apoptotic bodies are constructed of cell fragments and consist of organelles, cytoplasm and chromatin. (E) The final stage of apoptosis is apoptotic bodies phagocytosis.

Figure 2

Various signals activate autophagy. The target of these signals is ULK 1 complex, which includes ULK1, FIP200, ATG13 and ATG101 protein. During autophagy fragment of cytoplasm is surrounded by C-shaped double-membrane (A), while autophagosome is being created as the result of connection of two membrane ends (B). Afterwards autophagosome fuses with lysosome. The resulting vesicle is known as an autophagolysosome (C). In this vesicle the degradation of macromolecular substrates for into their basic constituents occurs (D).

Figure 3

The formation of neoplastic stem cells and the mechanism of cancer formation and its metastases. The development of a tumour is usually sequential. After the appearance of the first neoplastic cells, i.e., both stem cells and nonstem cells, the tumour develops gradually. In the next stage, the process of angiogenesis begins, and as a result of the formation of blood vessels, the invasive cells can move to other regions of the body.

Figure 4

Comparison of functionality of normal stem cell niche and cancer stem cells niche. A niche of stem cells under physiological circumstances provides the cells with conditions in which both cell differentiation and cell proliferation are inhibited. Only during the regeneration of the tissue in which the stem cells are located, a transient signal for proliferation is activated. When appropriate mutations of genetic material develop in the stem cell, they start to proliferate in an uncontrolled way. Another hypothesis assumes that as a result of such a mutation, the niche of the stem cells provides uninterrupted signals that initiate the proliferation and growth of the stem cells. As a result, a large pool of progenitor cells is created, which have a genetic mutation.

Figure 5

Two basic theories on the formation of cancer stem cells. In the theory assuming a hierarchical model of CSC formation, it is genetic and epigenetic transformation that leads to the formation of progenitor cells and cancer stem cells. The cells processed in this way undergo further transformations, which ultimately lead to the development of a tumour. Another theory, assuming the “evolution” of cancer stem cells, assumes that the whole process begins by induction of EMT, either as an element of the development of the disease or as a result of the activity of selected signals coming from the microenvironment of the tumour. Epithelial-to-Mesenchymal transition (EMT) is a natural process that triggers the development of the tumour, it determines changes in cell polarity and cell-cell contact.

Figure 6

Role of the PINK1/Parkin pathway in induction of autophagy both in stem cells and differentiated cells. In a properly functioning mitochondria PINK1 is transported through the TOM/TIM23 translocase complex to the internal mitochondrial membrane. It is then disintegrated (due to the activity of two proteases, PARL and MPP), transported to cytosol and degraded. When mitochondria do not functioning properly (which manifests itself as a dysfunction of mitochondrial membrane potential), ANT inhibits the transport of PINK1 through the TIM23 translocase. As a result of this phenomenon PINK1 accumulates on the external mitochondrial membrane. Accumulation of PINK1 on the external mitochondrial membrane results in formation of complex consisting of PINK1 and TOM translocase, which results in autophosphorylation of PINK1 and its activation. The activated PINK1 phosphorises the ubiquitinated substrates located on the external mitochondrial membrane, which makes it possible to connect Parkin and its phosphorylation. Phosphorylated Parkin, in turn, contributes to the ubiquitination of subsequent proteins on the external mitochondrial membrane. The ubiquitinated proteins, in the other hand, are able to phosphorylate subsequent PINK1 molecules, thus creating a feedback loop, so that a malfunctioning mitochondrion is covered with phosphoubiquitin. Then mitophagic adapters Optineurin and NDP52 bind phosphoubiquitin chains. These proteins further bind the LC3 protein, which allows the initiation of mitophagy. At the same time PINK1 interacts with Beclin-1, Parkin and Ambra proteins, which contributes to the formation of autofagosome around the damaged mitochondria [182].

Figure 7

The influence of nutrient availability on the induction of autophagy. The decrease in availability of nutrients contributes to a decrease in mitochondrial activity, which in turn increases the ratio of AMP to ATP and contributes to an increase in intracellular NAD+ levels. The consequence of increasing the AMP to ATP ratio is the activation of AMPK. Moreover, AMPK is activated by deacetylation, which generates a feedback loop. Increased NAD+ level, in turn, increases sirtrulines activity, which causes deacetylation of LKB1 and AMPK and regulation of their functions. A downwards pointing arrow shows a decrease in the intensity of the process. An upward arrow indicates an increase in the intensity of the process described.