Summary
Exercise benefits the musculoskeletal system and reduces the effects of cancer. The beneficial effects of exercise are multifactorial, where metabolic changes and tissue adaptation influence outcomes. Mechanical signals, a principal component of exercise, are anabolic to the musculoskeletal system and restrict cancer progression. We examined the mechanisms through which cancer cells sense and respond to mechanical signals. Low-magnitude, high-frequency signals were applied to human breast cancer cells in the form of low-intensity vibration (LIV). LIV decreased invasion through matrix and impaired secretion of osteolytic factors PTHLH, IL-11, and RANKL. Furthermore, paracrine signals from mechanically stimulated cancer cells, reduced osteoclast differentiation resorptive capacity. Physically disconnecting the nucleus by knockdown of SUN1 and SUN2 impaired the ability of LIV to suppress invasion and production of osteolytic factors. LIV also increased cell stiffness; an effect dependent on an intact LINC complex. These data show that mechanical signals alter the metastatic potential of human breast cancer cells, where the nucleus serves as a mechanosensory apparatus to alter cell structure and intercellular signaling.
Footnotes
E-mail Addresses: xinyi{at}iupui.edu; laewrig{at}iu.edu; gpagnott{at}iupui.edu; gunesuzer{at}boisestate.edu; powell69{at}purdue.edu; jmwalla{at}iupui.edu; usankar{at}iupui.edu; clinton.rubin{at}stonybrook.edu; kmohamma{at}iu.edu; tguise{at}iu.edu; thompwil{at}iu.edu
Funding support: This study was supported by Department of Defense BC150678P1 (WRT), NIH AR069943-01 (WRT), NIH AR068332 (US), Department of Defense BC150678 (TAG)
Conflict of Interest: CTR has several issued patents related to the use of mechanical signals to regulate cell behavior, and is a founder of Marodyne Medical, LLC, a developer of LIV technology. All other authors have no conflicts of interest.