Stress Granules in Cancer

Abstract

The capacity of cells to organize complex biochemical reactions in intracellular space is a fundamental organizational principle of life. Key to this organization is the compartmentalization of the cytoplasm into distinct organelles, which is frequently achieved through intracellular membranes. Recent evidence, however, has added a new layer of flexibility to cellular compartmentalization. As such, in response to specific stimuli, liquid-liquid phase separations can lead to the rapid rearrangements of the cytoplasm to form membraneless organelles. Stress granules (SGs) are one such type of organelle that form specifically when cells are faced with stress stimuli, to aid cells in coping with stress. Inherently, altered SG formation has been linked to the pathogenesis of diseases associated with stress and inflammatory conditions, including cancer. Exciting discoveries have indicated an intimate link between SGs and tumorigenesis. Several pro-tumorigenic signaling molecules including the RAS oncogene, mTOR, and histone deacetylase 6 (HDAC6) have been shown to upregulate SG formation. Based on these studies, SGs have emerged as structures that can integrate oncogenic signaling and tumor-associated stress stimuli to enhance cancer cell fitness. In addition, growing evidence over the past decade suggests that SGs function not only to regulate the switch between survival and cell death, but also contribute to cancer cell proliferation, invasion, metastasis, and drug resistance. Although much remains to be learned about the role of SGs in tumorigenesis, these studies highlight SGs as a key regulatory hub in cancer and a promising therapeutic target.

Keywords: Cancer; Membraneless organelles; Stress adaptation; Stress granules.

Fig. 1

SGs are key regulators of tumor stress adaptation. Cancer cells are located in a complex microenvironment that is marked by high levels of stress stimuli (oxidative stress, ER stress, hypoxia, and nutrient deprivation). In order to survive under such adverse conditions, cancer cells must adapt. SG formation is one of the key strategies for cancer cells to adapt to the stress conditions. Recent evidence indicates that SGs may contribute to tumorigenesis by modifying gene expression and signal transduction programs that regulate cancer cell proliferation, invasion and metastasis, suppression of apoptosis, and chemotherapy resistance

Fig. 2

SG regulation by pro-tumorigenic signaling. Oncogenes (mutant KRAS) and activation of pro-tumorigenic pathways (mTORC1, HDAC6, HBP) promote SG formation through multiple molecular mediators. The SG regulators are involved in induction (blue arrows) or disassembly (green lines) of SGs