Autophagy as a Survival Mechanism or a Cause of Disease
Doctoral thesis
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http://hdl.handle.net/11250/2384371Utgivelsesdato
2016Metadata
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Sammendrag
Proper turnover of cellular components is crucial for all cells. If damaged or excessive content in
the cell is not removed at a sufficient pace, normal cell functions may be compromised. The same
may occur if the degradation of cellular components occurs at a rate that cannot be balanced by
anabolic pathways. Autophagy is a major catabolic process that orchestrates the degradation of
cytosolic components ranging from proteins and lipids, to organelles such as mitochondria. If
correctly regulated, autophagy contributes to maintain proper homeostasis. Under certain
circumstances, the autophagy flux does not match the cellular need, leading to either too much or
too little autophagy. Here we have studied three different disease states where the speed of
autophagy may be improper; cancer cachexia, age-related macular degeneration (AMD) and
cancer.
Patients that suffer from cachexia lose substantial amounts of body mass, particularly skeletal
muscle. The condition is associated with reduced life quality and limited survival. Currently,
there are no available treatments to cure cachexia. The development of therapeutic strategies is
limited by a gap in our knowledge of the underlying mechanisms that cause the condition. The
development of cachexia is linked to a metabolic imbalance tipped in the favor of catabolic
decay. The individual contribution of autophagy in the development of the condition has not been
firmly determined, but the process is believed to be increased in tissues of cachectic patients. We
find that autophagy-accelerating bioactivity is present in sera from cancer patients that lose
weight and we identify IL-6 as an autophagy-accelerating signaling molecule that may contribute
to cachexia. Furthermore, we unravel underlying mechanisms that occur in the tumor or tumor
microenvironment that causes elevated level of IL-6.
AMD is a neurodegenerative disease of the eye and the leading cause of blindness in the western
world. AMD is characterized by the accumulation of protein and lipid deposits (drusen and
lipofuscin). Accumulation of such deposits is associated with insufficient autophagy. We find
that by increasing autophagy using the n-3 PUFA DHA, we can make cells more resistant to
stress situations that are associated with formation of cellular deposits and therefore disease
development. This suggests that autophagy acceleration may be preventive against diseases that
are characterized by accumulation of harmful cellular deposits and aggregates.
The regulation of autophagy in cancer cells have been a subject of much controversies. Generally
it is believed that autophagy will protect cells from conditions that may otherwise increase
mutation rates and contribute to carcinogenesis. In this regard, autophagy should be
downregulated for tumors to develop. On the other hand, once tumors have established, they may
depend on autophagy in order to survive. It is however, uncertain how and if autophagy may be
accelerated again post-tumor establishment. We find that the basal autophagy flux in a cancer cell
is a determinant as to whether the growth of cancer cells is affected by DHA. DHA can increase
the level of reactive oxygen species and other stress situations that may normally be encountered
by autophagy. In cancer cells with low basal autophagy, DHA compromises cell growth. This
urges the development of good methods that enable us to determine in vivo autophagy flux, as
that can help us identify tumors that could be growth inhibited by DHA.
This study emphasizes the importance of a correctly tuned autophagy regulation, as either too
much or too little autophagy may cause disease. Additionally, if we can determine the autophagy
flux during different disease states, we may be able to target this process in order to treat or
prevent disease.