Figure 1 G protein-mediated signaling pathway of GPCRs. Ligand-induced conformational change leads to activation of the
heterotrimeric G protein, resulting in dissociation of the
Gα subunit from the Gβγ subunits.
Downstream effects of secondary messengers lead to an ultimate cellular
response. Figure was made with adobe illustrator and adapted from Dorsam
and Gutkind (Robert T Dorsam & J Silvio Gutkind, 2007).
2.2 Aberrant GPCR expression in
cancer
Comparing to healthy tissues, aberrant expression of GPCRs are
frequently observed in several types of tumors (Kübler & Albrecht,
2018; Perez Almeria, Setiawan, Siderius, & Smit, 2021). Especially in
tumors of the neuroendocrine system, overexpression of GPCRs is highly
prevalent, such as MC2R, 5-HT4R, LHCGR, GnRHR, TRHR, GLP1R, GIPR, and
GRP101 (Lacroix et al. , 2024). It has also been reported that in
pancreatic ductal adenocarcinoma, overexpression of multiple GPCRs, such
as HRH1, LPAR5 and CCR6, tends to be more prevalent than common
oncogenic mutations such as KRAS and TP53 (Sriram, Moyung, Corriden,
Carter, & Insel, 2019). In addition, Arora et al. found that
almost every cancer subtype is characterized by a highly specific
GPCR-ligand co-expression signature, and they identified clusters of
GPCR-ligand pairs showing a prevalence of concordant upregulation or
downregulation across cancer subtypes. Furthermore, in some subtypes
featured with the co-downregulated GPCR axes, concomitant mutations of
several tumor suppressor genes are present. While in the concordantly
upregulated axes, cancer subtypes with Gα12/13prevalence are characterized by mutations of the KRAS, PIK3CA, and MLLT3
oncogenes. Importantly, they also found that the expression of GPCR
genes is associated with lower or higher survival of cases depending on
cancer subtype, while some receptors show consistent associations among
subtypes. For example, ADORA2A is associated with higher survival across
four cancer tissues (pancreas, breast, skin, and head and neck), while
GPCRs such as OXTR, ADORA2B, GPR3, FZD6 are invariably associated with
poorer survival. To be noted, there is not always consistency between
the association of receptor expression on patient survival with the
direct effects of receptor activation/inhibition on cancer cells. For
example, when HEPG2 cells were treated with either an ADORA2A or ADORA2B
inhibitor, they observed that the cell viability was significantly
decreased in a dose-dependent manner for both (C. Arora et al. ,
2024). Many factors including cancer subtype, receptor crosstalk, and
cell-cell interactions within the tumor microenvironment can play a
role, making drug effects on patients hard to predict. Despite the
complexity, these findings indicate that aberrant GPCR expression could
play an important role in cancer progression and prognosis.
2.3 GPCR signaling in cancer
development
In cancer, GPCR signaling can impact crucial characteristics of cancer
development, such as uncontrolled cell growth, achieving replicative
immortality, resisting apoptosis, initiating invasion and metastasis
(New & Wong, 2007; O’Hayre, Degese, & Gutkind, 2014). The role that
different downstream signaling pathways play is summarized below.