Cancer cell adaptability: turning ribonucleoprotein granules into targets

Abstract

Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies. RNP granules between stress and translationRegulating the expression of the genomic information is crucial to ensure cell identity and functionality. During transformation into cancer cells and throughout tumor progression, cells dynamically modulate the expression of their genomic information to adapt to environmental cues. Control of mRNA translation ensures the spatiotemporal adjustment of protein synthesis, and is often dysregulated in cancer cells to favor their adaptability [1]. In particular, regulation of translation initiation allows cancer cells to reprogram this activity towards essential mRNAs, such as those encoding oncogenes, to facilitate cell growth, proliferation, and survival [2]. Moreover, cancer cells must adapt to stress conditions in the TME, mainly through activation of the integrated stress response (ISR) [3,4] (Figure 1). This pathway controls translation initiation through eukaryotic initiation factor 2 (eIF2), which, once phosphorylated on its α subunit, prevents the formation of the ternary complex (eIF2:GTP: methionyl-initiator-tRNA) and consequently blocks translation initiation [5]. Four stress-sensor kinases can induce eIF2α phosphorylation, namely the PKR-like endoplasmic reticulum kinase (PERK), general control nonrepressible 2 (GCN2), heme-regulated inhibitor (HRI), and protein kinase R (PKR). The outcome of ISR activation is a global decrease in protein synthesis, while sparing the translation of some specific mRNAs such as that of transcription factor ATF4 [4]. Activation of this pathway, and the resulting selective translation, favor tumor progression following endoplasmic reticulum stress caused for instance by the hypoxic TME [6]. Furthermore, ISR activation by aberrant MYC expression enables cancer cells to adapt to this intrinsic stress by reprogramming translational programs. Consequently, the ISR prevents cancer cells from entering apoptosis and promotes both tumor progression [7,8] and escape from antitumor immunity [9,10].

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…This seemingly controversial, contradictory behavior may be readily explained by the fact that melatonin is a “smart”, pleiotropic molecule that selects the most appropriate strategy to protect the host organism [ 604 , 605 , 606 , 607 ]. The assembly of SGs is one of the major mechanisms used by cancer cells to adapt and survive under inhospitable, toxic microenvironments [ 608 , 609 ], as well as developing resistance to anticancer therapies [ 610 ]. Melatonin is known for its anticancer features, acting as a “broad-based metabolic buffer” to tune the cancer microenvironment [ 415 ].…”

Stress granule formation as a marker of cellular toxicity in lung organoids

“…Type II SGs are phospho-eIF2α-independent and are primarily formed through the inactivation of eIF4A. Type III SGs are triggered by UV light and glucose starvation and lack eIF3 [19][20][21][22][23]. Among them, the most well-studied pathway is one in which triggering eIF2α phosphorylation causes the subsequent aggregation of stalled translation initiation factors (Fig.…”

Stress granules promote chemoresistance by triggering cellular quiescence

“…Numerous studies indicate an intimate link between stress granules and cancer biology (Anderson et al ., 2015; Lavalée et al, 2021; Song and Grabocka, 2020). First, stress granules are found in a variety of tumors (Grabocka and Bar-Sagi, 2016; Somasekharan et al, 2015; Valentin-Vega et al, 2016).…”

“…However, how stress granules contribute to cancer biology is not well understood. One of the prevailing models is that stress granules help cancer cells adapt to a variety of cellular stress elicited by the tumor microenvironment and promote resistance to chemotherapeutic drugs (Anderson et al ., 2015; Lavalée et al ., 2021; Song and Grabocka, 2020).…”