Page 16 - GPD-2-2

Gene & Protein in Disease MOR in cancer

The in vitro use of morphine in the treatment of Lewis cells as well as inhibiting the production of blood
lung carcinoma cells (LLC) has been demonstrated to inhibit vessels . Interestingly, another study has shown that the
[96]
the nuclear translocation of HIF-1α and post-translational activation of MOR on the surface of vascular endothelial
modification/phosphorylation of HIF-1α by inhibiting cells could induce the production of NO by increasing
[97]
the hypoxia-induced mitochondrial p38 MAPK pathway, intracellular calcium concentration, which can promote
thus reducing the transcription and secretion of VEGF . the proliferation and migration of vascular endothelial cells
[92]
Therefore, angiogenesis in LCC could be inhibited by and increase their permeability. NO participates in tumor
blocking the HIF-1α/p38 MAPK pathway following MOR angiogenesis by endothelial constitutive NO synthetase
activation. Interestingly, Singleton et al. found contrary (ec-NOS) activation, cyclic guanosine monophosphate
[93]
results showing a significantly higher expression of MOR (cGMP) elevation, MAPK activation, and fibroblast growth
in lung cancer samples than in adjacent control tissues and factor 2 (FGF-2) expression (Figure 7) .
[98]
that the effect of MOR on tumorigenesis might be due to Therefore, by exploring the effect of MOR activation
increased VEGF expression (Figure 6). Similar results have on tumor angiogenesis, it may be possible to use MOR
been observed in a study of breast cancer patients, whereby as the target to achieve the purpose of treating tumors by
morphine induced metastasis formation by upregulation activating/inhibiting angiogenesis of certain cancer cells.
of urokinase plasminogen activator (uPA) expression
and induced angiogenesis and tumor progression by 3.3. Tumor immunity
transactivation of VEGF receptor . The tumor microenvironment (TME) plays a very important
[94]
[95]
NO plays a very important role in tumor angiogenesis . role in the occurrence and development of cancer [99,100] .
Research results have suggested that morphine can reduce In the tumor microenvironment, activated inflammatory
mitochondrial membrane potential by binding to MOR cells release multiple inflammatory mediators and
on vascular endothelial cells, promoting the production of molecules, such as interleukin-2 (IL-2), IL-6, and tumor
NO, stimulating the expression of pro-apoptotic factors Bak necrosis factor alpha (TNF-α), transforming the tumor
and Bax, thereby activating caspase-3 and caspase-7, and microenvironment into an environment that is more
ultimately inducing the apoptosis of vascular endothelial suitable for cancer cell survival [101] . Opioids have a dual

Figure 6. A model of possible mechanisms affecting tumor angiogenesis after MOR activation. The
treatment of morphine activates MOR, reduces hypoxia, induces p38 MAPK, and thus HIF-1α activation.
cAMP: Cyclic adenosine monophosphate; HIF-1α: Hypoxia-inducible factor 1 alpha; HRE: Hypoxia response element; MAPK: Mitogen-activated protein
kinase; MOR: Mu (µ)-opioid receptor; ROS: Reactive oxygen species; VEGF: Vascular endothelial growth factor. Image created with BioRender.com.

Volume 2 Issue 2 (2023) 10 https://doi.org/10.36922/gpd.282