• norsk
    • English
  • norsk 
    • norsk
    • English
  • Logg inn
Vis innførsel 
  •   Hjem
  • Fakultet for medisin og helsevitenskap (MH)
  • Institutt for klinisk og molekylær medisin
  • Vis innførsel
  •   Hjem
  • Fakultet for medisin og helsevitenskap (MH)
  • Institutt for klinisk og molekylær medisin
  • Vis innførsel
JavaScript is disabled for your browser. Some features of this site may not work without it.

Autophagy as a Survival Mechanism or a Cause of Disease

Pettersen, Kristine
Doctoral thesis
Åpne
Fulltext not available (Låst)
Permanent lenke
http://hdl.handle.net/11250/2384371
Utgivelsesdato
2016
Metadata
Vis full innførsel
Samlinger
  • Institutt for klinisk og molekylær medisin [2017]
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.
Utgiver
NTNU
Serie
Doctoral thesis at NTNU;2016:52

Kontakt oss | Gi tilbakemelding

Personvernerklæring
DSpace software copyright © 2002-2019  DuraSpace

Levert av  Unit
 

 

Bla i

Hele arkivetDelarkiv og samlingerUtgivelsesdatoForfattereTitlerEmneordDokumenttyperTidsskrifterDenne samlingenUtgivelsesdatoForfattereTitlerEmneordDokumenttyperTidsskrifter

Min side

Logg inn

Statistikk

Besøksstatistikk

Kontakt oss | Gi tilbakemelding

Personvernerklæring
DSpace software copyright © 2002-2019  DuraSpace

Levert av  Unit