The role of AP-1 in self-sufficient proliferation and migration of cancer cells and its potential impact on an autocrine/paracrine loop
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Sherif Abd El-Fattah Ibrahim1,2,*, Aierken Abudu1,*, Eugenia Johnson1, Neelum Aftab1, Susan Conrad1 and Michele Fluck1
1Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
2Department of Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
*These authors have contributed equally to this work
Sherif Abd El-Fattah Ibrahim, email: [email protected]
Aierken Abudu, email: [email protected]
Keywords: cancer; AP-1; self-sufficient growth; autocrine; paracrine
Received: February 27, 2018 Accepted: August 13, 2018 Published: September 28, 2018
Activating protein-1 (AP-1) family members, especially Fra-1 and c-Jun, are highly expressed in invasive cancers and can mediate enhanced migration and proliferation. The aim of this study was to explore the significance of elevated levels of AP-1 family members under conditions that restrict growth. We observed that invasive MDA-MB-231 cells express high levels of Fra-1, c-Jun, and Jun-D during serum starvation and throughout the cell cycle compared to non-tumorigenic and non-invasive cell lines. We then analyzed Fra-1 levels in additional breast and other cancer cell lines. We found breast and lung cancer cells with higher levels of Fra-1 during serum starvation had relatively higher ability to proliferate and migrate under these conditions. Utilizing a dominant negative construct of AP-1, we demonstrated that proliferation and migration of MDA-MB-231 in the absence of serum requires AP-1 activity. Finally, we observed that MDA-MB-231 cells secrete factors(s) that induce Fra-1 expression and migration in non-tumorigenic and non-metastatic cells and that both the expression of and response to these factors require AP-1 activity. These results suggest the presence of an autocrine/paracrine loop that maintains high Fra-1 levels in aggressive cancer cells, enhancing their proliferative and metastatic ability and affecting neighbors to alter the tumor environment.
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