Stress granules, P-bodies and cancer

Abstract

Cancer cells are exposed to adverse conditions in the tumor microenvironment, and utilize post-transcriptional control mechanisms to re-program gene expression in ways that enhance cell survival. Stress granules and processing bodies are RNA-containing granules that contribute to this process by modulating cellular signaling pathways, metabolic machinery, and stress response programs. This review examines evidence implicating RNA granules in the pathogenesis of cancer and discusses their potential as targets for anticancer therapies. This article is part of a Special Issue entitled: Translation and Cancer.

Keywords: Apoptosis; Cancer; P-body; Post-transcriptional regulation; Stress granule; Stress response.

Figure 1. RBP-RNA granules interplay on the target mRNA

Under steady-state conditions, mRNA is actively engaged into translation as a part of polysome and in the form of translationally-competent mRNP consisting of several translation initiation factors (such as cap-binding complex eIF4F and multi-subunit eIF3) and mRNA-bound RBPs (such as poly(A)-bound PABP). In response to cell-intrinsic and extracellular changes mRNA translation is arrested and transcript can be routed from the polysomes to SGs (blue arrows) or PBs (red arrows). Transcripts destined for assembly into PBs are first deadenylated by one or more mRNA deadenylases (PAN2/3 and CCR4/NOT are shown as examples). This causes the release of PABP molecules from the mRNA poly(A) tail, and the remodeling/decircularization of the mRNP which primes it for decapping. PB-associated decay enzymes subsequently may mediate mRNA decapping and decay within PBs. In contrast, transcripts assembled into SGs retain their poly(A) tails and associated PABP. Stresses, which may trigger phosphorylation of eIF2α (red shading) or not (such as inhibition of eIF4A, aqua shading), disrupt translational initiation of the mRNA, resulting in the runoff of ribosomes and the accumulation of stalled mRNPs. Binding of mRNAs by aggregation-prone RNA binding proteins (such as TIA-1, G3BP1) subsequently promotes its coalesce into SGs. Certain decay-promoting proteins (TTP, BRF1) can promote deadenylation and decay of SG-associated transcripts in tandem with promoting SG-PB fusion/interactions. Multiple additional proteins and signaling molecules associate with SGs or PBs once they are formed, depending on conditions.

Figure 2. RNA granules and tumor microenvironment

Collective contributions from the different stress-associated conditions and surrounding cellular environment result in the unique niche where cancer cells exist, known as the tumor microenvironment (yellow). The tumor microenvironment changes dynamically during tumor progression, which requires constant adaptation of cancer cells to the changing intracellular and extracellular conditions. Hypoxia and nutrient starvation force cells to alter their metabolism/cellular energetics ultimately causing chronic ROS production that has multiple effects on cancer cell (patho)physiology. Chronic ER stress results from the imbalance between increased protein synthesis due to the high demands on cancer cell proliferation and ER capacity often. These stresses, often augmented by chemotherapy, trigger formation of PBs/SGs, spatial manifestations of ISR (Integrative Stress Response) that orchestrates cellular adaptation to changing conditions. The integration and balanced management of these cancer-associated stresses through SGs and PBS modulate multiple physiological responses (bottom red panel) including activation of anti-apoptotic, pro-survival mechanisms, enhanced tumor growth, modulation of immune responses, promotion of angiogenesis and/or activation of a novel developmental regulatory program/transformation referred to as the “epithelial-mesenchymal transition” (EMT). Multiple RNA-binding proteins with signaling properties (Ago2, RCK, TTP, YB-1, G3BP) and signaling molecules (RACK1, TRAF2, Raptor, mTOR) dynamically associate with SGs and PBs (double-headed arrows). They may transduce signals incoming from tumor microenvironment (yellow) to the physiological responses (bottom red panel), thus mediating both short- and long-term adaptations critical to tumor growth and metastasis. For other details, see text.