Investigation of the Role of Tensile Forces in Cellular Response to Chemotherapeutic Agents

Abstract

Research using in vitro cell cultures are frequently conducted under static growth conditions. Cells growing in vivo, however, grow in a highly dynamic and interactive environment, where they receive cues in the form of mechanical stimuli from their surroundings. Lung cells, for example, are continually exposed in vivo to a cyclic tensile stretch during normal inhalation and exhalation. The absence of a mechanically representative environment could have important implications for research and development, particularly in the context of drug discovery. We hypothesize that tensile (mechanical) forces applied to two non-small cell lung cancer cell lines, bronchoalveolar H358 cells and alveolar A549 cells, play an important role in determining cellular response to chemotherapeutic agents. In order to investigate changes resulting from exposure to tensile stretch, we first looked at changes in proliferation and expression of a few cellular markers associated with epithelial-mesenchymal transition (EMT). Next, we looked at changes in cell cycle distribution and expression of a few cell-cycle checkpoint proteins. Finally, we studied the effect of a tensile force on the efficacy of three chemotherapeutic agents. We found that a tensile force significantly reduces cellular proliferation and causes significant shifts in cell cycle distribution. Mechanically active culture environments led to decreased efficacy of cisplatin and increased efficacy of Zactima. These results indicate that a mechanically active culture environment does impact cell survival and protein expression, and has important implications in the context of the discovery and screening of new antitumor drug therapies.