Description
TitleABCG2-augmented autophagy
Date Created2021
Other Date2021-05 (degree)
Extent1 online resource (xi, 114 pages)
DescriptionThe multidrug transporter ABCG2 is best known for its ability to efflux a wide variety of compounds, but its aberrant overexpression in cancer can lead to multidrug resistance. ABCG2 plays a role in tumor cell survival by enhancing the rate of autophagy, a conserved, catabolic recycling process that breaks down damaged proteins and cellular organelles to form cellular building blocks. By augmenting autophagy, ABCG2 can enhance cell survival in the face of non-substrate stresses such as nutrient deprivation and radiation.
Conflicting reports have emerged about the impact of ABCG2 expression on cancer cell migration. Likewise, autophagy can play either a pro-metastatic or anti-metastatic role, depending on the context. Further investigation into how ABCG2-augmented autophagy may impact a highly complex and coordinated process such as cell migration is warranted.
In this study, we validated that ABCG2 overexpression enhances cancer cell migration and invasion in vitro. This is correlated to an increased expression of matrix metalloproteases and other critical cell adhesion molecules such as Focal Adhesion Kinase and Paxillin. Cell migration is attenuated when pharmacologic or genetic approaches impair either ABCG2 or autophagy. Most importantly, we observed that in the absence of functional autophagy, ABCG2 overexpression could not augment cell migration. These results show that ABCG2 expression enhances cell migration by augmenting autophagy.
ABCG2-augmented autophagy appears to regulate cell migration by altering the levels of active Rho A and Rac GTPases. Through a network of downstream signaling molecules, these proteins, and their antagonistic effect on each other, regulate cellular motility. The process of autophagy degrades the GTP-bound form of Rho A, so we hypothesized that in ABCG2 overexpressing cells, the levels of this active form of Rho A would be lower. We found that indeed, ABCG2 overexpressing cells had lower levels of active Rho A and reduced phosphorylation of myosin light chain, a downstream target of Rho A. Not expectedly, these cells also expressed higher levels of GTP-bound Rac, which is known to promote mesenchymal migration in cells. Indeed, when autophagy was inhibited, a decrease in GTP-bound Rac and an increase in GTP-bound Rho A were observed in the ABCG2 overexpressing cells. In addition to the prior observation that autophagy inhibition retards cell migration, these results show that ABCG2 overexpression enhances cell migration by tipping the balance of Rho A – Rac towards higher Rac activity and consequently increased mesenchymal migration. This study provides a novel insight into the mechanisms by which ABCG2 expression enhances cell migration which may translate to increased metastasis in vivo and in patients. Thus treatments that downregulate ABCG2 may not only help reverse multidrug resistance but may also have anti-metastatic effects.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.