Inhibin-[beta]-E signaling pathway promotes cancer cells adaptation to metabolic stress

Dan He

doi:10.17918/etd-7707

Metabolic stress frequently occurs in lesions of high impact diseases such as cancer, heart disease and stroke. In most ischemic tissues, the cells exposed to metabolic stress will undergo various injury and even cell death. In tumors cells the decreased supply of nutrients caused by defective angiogenesis cannot meet the increased demand of rapid cell proliferation, causing metabolic stress. Unlike normal tissues, tumors usually are able to adapt to such stress by adaptive metabolism. A better understanding of the molecular mechanisms underlying tumor cell adaptation to metabolic stress may provide important insight into novel therapies to treat both cancer and ischemic disorders. Two most noticeable adaptive metabolisms of tumors are increased glycolysis and glutaminolysis, reflecting the increased demands for carbon and nitrogen sources to support proliferative biosynthesis. Using glutamine depletion and glucose depletion as models of metabolic stress, previous studies from our lab demonstrated that acute glutamine and glucose depletion caused cell growth arrest and eventually cell death. However, by culturing Hep3B cells in glutamine-free media with ammonia as an alternative source of nitrogen, our lab has successfully established MM01, which is capable of perpetual survival in glutamine free media with ammonia, but assumes a slow growing phenotype, thus representing a model adapted to long-term metabolic stress. Using microarray-based genome-wide gene expression profiling to study the gene expression reprogramming in the adapted MM01 cells, we obtained the initial evidence of functional activation of Smad2/3 in MM01 cells. However, the underlying molecular mechanism and roles of Smad2/3 activation in cell adaptation to metabolic stress remain unclear. In this thesis study, I have substantiated that metabolic stress triggers Samd2 phosphorylation, which in turn, stimulates the expression of cell cycle inhibitor p15, providing a link to the slow growing phenotype. Moreover, I found that the expression of inhibin-[beta]-E, a member of the TGF-[beta]-superfamily was upregulated upon metabolic stress. Overexpression of inhibin-[beta]-E was sufficient to trigger Smad2/3 activation; whereas loss of inhibin-[beta]-E impaired Smad2/3 activation when cells exposed to metabolic stress. Importantly, I found that cells lack of either inhibin- [beta]-E or ACVR1B lost the potential to adapt to chronic glutamine insufficiency. Furthermore, I demonstrated that metabolic stress collectively led to ER stress, which in turn was sufficient to enhance inhibin-[beta]-E promoter activity. Taken together, my data support a model that metabolic stress enhances inhibin-[beta]-E expression via ER stress. By an autocrine or paracrine modal of action, dimeric inhibin-[beta]-E (activin E) activates Smad2/3, thus facilitating cell survival by slowing down biosynthesis and proliferation. These findings may pave a way towards novel therapeutic strategies for both cancer and ischemic disorders.

Inhibin-[beta]-E signaling pathway promotes cancer cells adaptation to metabolic stress

Files and links (1)

Abstract

Metrics

Details

Inhibin-[beta]-E signaling pathway promotes cancer cells adaptation to metabolic stress

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media