Abstract B119: Blocking metabolic stress response with genetic knockdown and selective ligands of sigma-1 receptor in cancer cells

In this study we examined whether Sig1R sustains proliferation, survival and tumorigenic properties of human cancer cells. Knockdown of Sig1R using small interfering RNA (siRNA) in human prostate and lung cancer cell lines had profound effect on proliferation, clonogenic capability and tumor-sphere formation, indicating reversal of the tumorigenic and stem-like phenotype in absence of Sig1R. Next, in the attempt to discover pharmacological agents that could phenocopy the effects of the genetic knockdown in cancer cells we tested a series of structurally diverse Sig1R ligands selected for high affinity and selectivity for the receptor. We identified various Sig1R ligands that behaved as antagonists of the receptor functions in cancer cells inhibiting clonogenicity and tumor-sphere formation. Effective concentrations of the ligands were in the micromolar range (1-10 μM). At these doses, Sig1R antagonistic ligands almost completely suppressed clonogenic and tumor sphere forming capability of cancer cells. Furthermore, whereas cell proliferation and viability under standard culture conditions were minimally affected by Sig1R ligands, their effects were more pronounced under glucose starvation, a condition that causes metabolic stress in cancer cells. Notably, both Sig1R knockdown and pharmacological antagonists led to impaired mitochondrial function, which was more evident under glucose starvation. Thus, the absence of functional Sig1R reduced mitochondrial activity and adapta...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: New Molecular Targets: Poster Presentations - Proffered Abstracts Source Type: research