Sigma-1 Receptor Control Tumorigenic And Stem Cell-Like Phenotype In Human Cancers

Tumor-initiating stem-like cancer cells drive tumor progression, metastasis and treatment failure. Understanding the pathways driving self-renewal and expansion of cancer stem-like cells (CSCs) in human cancers may provide actionable therapeutic targets for developing novel treatment strategies. Metabolic reprogramming and mitochondrial homeostasis are emerging as key features of CSCs. The sigma-1 receptor (Sig-1R) is a ligand-activated chaperone protein localized at the ER-mitochondria membrane and involved in inter-organelle signaling, mitochondrial homeostasis and stress response. Sig-1R is up-regulated in many human cancers, although its role in tumorigenesis is unclear. Here, we examined the role of Sig-1R on survival and expansion of cancer cells with stem-like properties using genetic knockdown and selective pharmacological antagonists. Transient and stable depletion of Sig-1R using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs), respectively, affected clonogenic and tumor-sphere forming capability of prostate cancer cell lines. Cell proliferation and viability under standard culture conditions were minimally affected. Selective high affinity Sig-1R antagonists also suppressed clonogenicity and tumor-sphere formation, reproducing the effects of genetic depletion. Notably, stable Sig-1R knockdown with shRNAs drastically reduced development of tumor xenografts in mice, indicating a reversal of tumorigenic and stem-like properties upon depletion of Sig-1R. Sig-1R knockdown impaired mitochondrial function with reduced mitochondrial membrane potential (flow cytometry JC-1 assay) and respiratory capacity (Seahorse Mito Stress assay). These effects were more evident under metabolic stress induced by glucose starvation and were associated with drastic changes in morphology and intracellular distribution of mitochondria. Similar metabolic effects were seen with selective Sig-1R antagonists. These findings indicate that Sig-1R sustains tumorigenic properties by enhancing mitochondrial homeostasis and metabolic adaptability of stem-like cancer cells ensuring their long-term survival and self-renewal capability. Targeting the Sig-1R with selective antagonists could be an innovative approach to cancer treatment capable of preventing survival and expansion of tumor-initiating stem-like cancer cells in human cancers. Citation Format: Gianluca Civenni, Martina Marchetti, Shusil Pandit, Celeste De Monte, Federica Sereni, Jessica Merulla, Sabrina Zadic, Marco Losa, Sara Allegrini, Domenico Albino, Sarah Mapelli, Erik Laurini, Bernhard Wunsch, Sabrina Pricl, Giuseppina M. Carbone, Carlo V. Catapano. Sigma-1 receptor control tumorigenic and stem cell-like phenotype in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2900. doi:10.1158/1538-7445.AM2017-2900