Medicine by Alexandros G. Sfakianakis: From Then ‘till Now: The History of Autophagy and Cancer Research

Τετάρτη 27 Δεκεμβρίου 2017

From Then ‘till Now: The History of Autophagy and Cancer Research

By Christina Towers, PhD.

The fundamental process that cells use to degrade damaged cytoplasmic material and recycle nutrients is called autophagy. This term was first coined by the Belgium biochemist Christian de Duve stemming from the Greek translations of "auto" meaning "self" and "phagy" meaning "eat", thus: "autophagy" translates to "eating one's self". de Duve's seminal work identified the previously unknown organelle, the lysosome and transpired in a Nobel Prize in Medicine in 1974¹.

Almost 4 decades after de Duve discovered the lysosome, Yoshinori Ohsumi and his group in Japan started cloning autophagy specific genes from Sachharamyces cerevisiae, the first being Apg13 (ATG1 in humans)². Ohsumi's group continued to characterize most of the complex autophagy pathway in yeast as well as higher eukaryotes, and elucidated dozens of autophagy specific genes (ATGs) like Apg8 lipidation (LC3 in humans) and the ubiquitin-like conjugation systems involving Apg3, Apg7, Apg10, and Apg12 (ATG3, ATG7, ATG10, and ATG12 in humans)^3,4.

Autophagy Induction

GAPR-1/GLIPR2 is a negative regulator of autophagy and binds Beclin 1 to inhibit autophagy. In the presence of Tat-D11 peptides, Beclin 1 bound to GAPR-1 is released allowing Beclin 1 to mediate autophagosome formation and autophagy induction.

By the end of the 1990's the basics of the autophagy process were becoming more clear, however, there was almost no understanding of how this process might function in human disease. Beth Levine's group was the first to associate autophagy with cancer, as they described the core autophagy protein, BECLIN1, as a putative tumor suppressor which they found to be lost in most tumors⁵. While the tumor suppressive functions of BECLIN1 are still up for debate, these seminal studies ignited the field of autophagy in cancer fueling the hundreds of publications that would follow. There is now a general consensus in the field that autophagy may inhibit tumorigenesis at early stages during tumor development, but in an established tumor, autophagy is tumor-promotional, ultimately suggesting that autophagy may be a viable therapeutic target⁶. A critical discovery in the field, although now only noted by hindsight, also occurred around this same time in the late 1990s: that is the discovery that the anti-malarial therapy, Chloroquine, accumulates in the lysosome and is a potent inhibitor of autophagy⁷.

Fast forward almost 20 years, and over that time the number of publications in the field of autophagy has risen from just about 100 publications per year in 1990 to over 2500 publications per year in 2013⁸. The importance of the field was highlighted in 2016 with a Nobel Prize to Yoshinori Ohsumi for his work that first characterized the pathway in yeast. de Duve's discovery of the lysosome in 1963 laid the ground work for the 5 plus decades of research that would follow characterizing autophagy in normal biology, understanding its role in disease, and finding ways to target it, all of which have culminated in over 50 current clinical trials targeting autophagy with Chloroquine (and its derivatives), the majority of which focus on cancer.

Explore the Autophagy Interactive Pathway

Christina Towers, PhD

References

Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nature reviews. Cancer, doi:10.1038/nrc.2017.53 (2017).
Funakoshi, T., Matsuura, A., Noda, T. & Ohsumi, Y. Analyses of APG13 gene involved in autophagy in yeast, Saccharomyces cerevisiae. Gene 192, 207-213 (1997).
Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488-492, doi:10.1038/35044114 (2000).
Mizushima, N., Sugita, H., Yoshimori, T. & Ohsumi, Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 273, 33889-33892 (1998).
Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672-676, doi:10.1038/45257 (1999).
Towers, C. G. & Thorburn, A. Therapeutic Targeting of Autophagy. EBioMedicine, doi:10.1016/j.ebiom.2016.10.034 (2016).
Murakami, N. et al. Accumulation of tau in autophagic vacuoles in chloroquine myopathy. J Neuropathol Exp Neurol 57, 664-673 (1998).
Ohsumi, Y. Historical landmarks of autophagy research. Cell Res 24, 9-23, doi:10.1038/cr.2013.169 (2014).