161 - Redox-Dependent Calcium-Mediated Signaling Networks That Control the Senescence-Associated Secretory Phenotype

Abstract

Cellular senescence has evolved as one of the protective mechanisms to arrest the growth of cells with oncogenic potential. While senescent cells lose the ability to divide, they remain metabolically active and adapt a senescence-associated secretory phenotype (SASP). The SASP is central to the progression of several age-associated disease pathologies perpetuated by inflammation. A key modulator of SASP is the pro-inflammatory cytokine interleukin-1 alpha (IL-1α) whose expression and activity is responsive to the senescence-associated (SA) oxidant production and the accompanying disruption of calcium (Ca2+) homeostasis. Members of the Transient Receptor Potential (TRP) channel family control cellular Ca2+ and are sensitive to activation by steady state hydrogen peroxide (ss-H2O2). This study aims at determining the molecular identity of the Ca2+ channel(s) that control the activity of the SASP regulator IL-1α. Using primary IMR-90 human fetal lung fibroblasts as a cellular senescence model, we have begun to explore the likely channel responsible for increased Ca2+ entry in senescent cells. We establish the idea that the redox-responsive TRPM2/TRPC5 channel activity is compromised during senescence due to desensitization by increased ss-H2O2 and TRPC6 channel activity is elevated to compensate for this loss of H2O2-responsive channel activity, thereby modulating SA dysregulation of Ca2+. We hypothesize that modification of this Ca2+ channel in the senescent cells can limit the downstream processing and regulation of IL-1α thereby reversing the SASP. This can establish a new paradigm of communication between the mitochondrial reactive oxygen species (ROS), cytosolic Ca2+ and nuclear IL-1α in senescence. Also, IL-1 α and TRPC6 have been shown to be independently regulated by mechanistic target of rapamycin (mTOR) signaling, a nutrient sensing pathway involved in regulation of aging processes. Overall, these studies identifying the TRPC6-mediated IL1α regulatory loop in senescence have the potential to identify new therapeutic approaches that limit the disease promoting properties of senescent cells without impairing their ability to defend against oncogenic insult.