Abstract
Attachment to the matrix is critical for the survival of adherent cells, whereas detachment triggers death by apoptosis. Therefore, solid tumors must acquire the ability to survive the stress of matrix-detachment to transit through circulation and seed metastases. Although a central role for energy metabolism in cancer progression is well established, what distinguishes its role in the cellular state of the matrix-deprived form compared to the matrix-attached form is not fully understood yet. Using an in vitro transformation model dependent on simian virus 40 (SV40) small t (ST) antigen for cellular survival and proliferation in matrix-deprived conditions, we demonstrate that 5′-adenosine monophosphate-activated protein kinase (AMPK) activity is elevated and sustained under matrix-deprived conditions in ST-expressing fibroblasts. Additionally, these cells display elevated energy (ATP) levels under matrix-deprived conditions in contrast to cells lacking ST expression. The elevated ATP levels are coupled to increased levels of proline in ST-expressing cells, as revealed by metabolomics studies. The AMPK-dependent upregulation of proline oxidase, an enzyme of proline degradation, is a key link for elevated ATP levels. This functional link is further established by proline supplementation concomitant with AMPK activation in matrix-deprived cells lacking ST antigen, yielding ATP and enhancing survival. Thus, our data establishes a key role for AMPK-dependent regulation of proline metabolism in mediating energy homeostasis and promoting survival of matrix-deprived cells. These findings identify key markers that distinguish the metabolic states of matrix-detached and matrix-attached transformed cells and have implications in developing novel therapeutic strategies for specifically targeting matrix-detached metastasizing cancer cells.
Highlights
The spread of cancer by metastasis is the major cause of cancerassociated death
In this study, using in vitro transformed human fibroblasts that are dependent on the simian virus 40 (SV40) small t (ST) antigen for their matrix-deprived survival and growth (Rangarajan et al, 2004), we show that the presence of ST antigen helps sustain AMPK activity in matrix-deprived cells, which in turn helps maintain ATP levels
These results suggested a role for ST antigen in the survival and proliferation of matrix-deprived cells
Summary
Advancement of cancer from the formation of a primary tumor to the seeding of metastases comprises a complex series of events that encompass multiple hurdles to be overcome by cancer cells (Mehlen and Puisieux, 2006). A fundamental requirement of cancer cells to seed metastases is the ability to withstand the stress of matrixdeprivation. Transformed cancer cells evade anoikis and survive under matrix-deprived conditions, attaining anchorage-independence (Paoli et al, 2013). This, in turn, is an important hallmark property of cancer cells that endows them with the ability to survive in circulation and seed metastases at distant locations (Mehlen and Puisieux, 2006). A better understanding of the mechanisms that enable cancer cells to survive the stress of matrix-deprivation can help in identifying therapeutic strategies to prevent metastasis
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