Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

Abstract

G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.

Role of Calcium Homeostasis in Modulating EMT in Cancer

“…These MMPs enhance motility by breaking down proteins in the basement membrane and extracellular matrix, to allow cells to metastasize away from the primary tumor. Recently, several types of the GPCR, protease-activated receptor (PAR), have been found to be upregulated in cancer [ 36 ]. Interestingly, the overexpression of PAR was found to induce EMT via TGF-β signaling, leading to the loss of cell polarity [ 37 ].…”

“…While some of these mutations increased the agonist effect, others reduced or completely eliminated receptor activation, demonstrating how minute changes in the protein sequence can completely transform this GPCR’s capabilities. Recent work has also substantiated GPCRs’ role in the upregulation of EMT transcription factors, such as ZEB, Snail, and Twist, which are involved in numerous transitions, including cell polarity, cytoskeleton remodeling, migration, and invasion [ 36 , 40 ]. It has been challenging to delineate the actual function and various ligands of all GPCRs, due to their extensive crosstalk with the proteins and pathways that perform the vast majority of cellular functions.…”

Traditional Chinese Medicines as Effective Reversals of Epithelial-Mesenchymal Transition Induced-Metastasis of Colorectal Cancer: Molecular Targets and Mechanisms

“…Recently, numerous researches have confirmed that EMT progression is mainly mediated by multiple key signal transduction pathways containing transforming growth factor-β (TGF-β)/Smads, Wnt/β-catenin, phosphatidylinositol 3-kinase (PI3K)/Akt, Notch, and NF-κB signaling pathways (De Rosa et al, 2015;Vinson et al, 2016;Mishra et al, 2017;Tan et al, 2017;Song et al, 2020). There are multiple specific EMTtranscription factors (EMT-TFs) involved in the EMT process undergoing tumor metastasis, including Snail, Slug (Snai2), ZEB1/2, and Twist (Goossens et al, 2017;Williams et al, 2019;Feng et al, 2020;Kumari et al, 2021;Lu et al, 2021), they closely acted pleiotropically and in diverse combinations to down-regulate epithelial marker E-cadherin, while upregulating the mesenchymal signatures such as N-cadherin, vimentin, and fibronectin, and thus promoting the tendency of cancer cells to mesenchymal-like features (Dongre and Weinberg, 2019), which ultimately contribute to the initiation of EMT process. The transcriptional modulation of multiple signal pathways with crosstalk molecular mechanisms closely involved in EMT regulation are summarized as indicated in Figure 1.…”

Metastasis and MAPK Pathways

“…This topic was reviewed previously in [ 141 ]. EGFR is the most well-known growth factor receptor that interacts with G protein-coupled receptors (GPCRs) and is involved in the regulation of tumor development, invasion, and progression in a variety of malignancies [ 142 ].…”