MTOR is a Mechanistic Target of Muscle and Cancer Cross‐Talk with Exercise

Abstract

INTRODUCTIONThe mTOR signaling pathway regulates growth and cellular proliferation, which is vital for normal cell function. However, when this pathway is dysregulated, such as in cancer, it can lead to hyperactivation of signals which promote cell proliferation and protect against cell death. DEPTOR, a potent endogenous mTOR inhibitor, generally has low expression in many cancers. We have unique preliminary findings that myokines released during electrically‐stimulated muscle contraction of hemicorpus‐hindlimb perfused rats affect mTOR signaling and DEPTOR protein content in breast cancer cells. When MCF‐7 cancer cells were treated with perfusate collected during muscle contraction, a significant inhibition of proliferation was noted alongside diminished mTOR activity and elevated DEPTOR expression.PURPOSETo investigate changes in anabolic signaling and resultant protein synthesis rates in MCF7 human breast cancer cells exposed to pharmacologically administered mTOR inhibitors.METHODSMCF7 cells were cultured in 10cm plates until 60% confluence in standard Growth Media (GM). Cells were treated with either Rapamycin or Torin1 inhibitors (100nM or 250nM, respectively) in 10 ml of GM. Cells for protein synthesis analysis were additionally treated with heavy water (2H2O) to yield a 4% final volume. All groups were incubated in respective media for 24hrs and prepped for western blot or rates of protein synthesis analysis.RESULTSDEPTOR protein expression increased in both rapamycin and Torin1 treated cells (2‐fold & 7‐fold, respectively). Both Rapamycin and Torin 1 treated cells show decreased daily rates of protein synthesis compared to cell control (14.41, 9.09 vs 20.46 %/d, respectively).CONCLUSIONOur results suggest that diminished DEPTOR protein content and concomitant mTOR hyperactivity are important contributors to MCF7 cellular proliferation, in culture. Pharmacological administration of mTOR inhibitors suppresses protein synthesis and consequent anabolic signaling, with a rescue of DEPTOR protein content, which, in part, is consistent with our previous findings using exercise perfusate.Support or Funding InformationThis work was funded in part by the College of Health and Education and the Huffines Institute for Sports Medicine at Texas A&M University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.