Aberrant Expression of OX1 Receptors for Orexins in Colon Cancers and Liver Metastases: an Openable Gate to Apoptosis

Abstract

Resistance to apoptosis is a recurrent theme in colon cancer. We have shown previously that the 7-transmembrane spanning receptor OX1R for orexins promotes robust apoptosis in the human colon cancer cell line HT29 through an entirely novel mechanism involving phosphorylation of tyrosine-based motifs in OX1R. Here, we investigated the status of OX1R in a large series of human colorectal tumors and hepatic metastases. All primary colorectal tumors regardless of their localization and Duke's stages and all hepatic metastases tested expressed OX1R mRNA and/or protein. In sharp contrast, adjacent normal colonocytes or hepatocytes as well as control normal tissues were negative. Next, we showed that nine human colon cancer cell lines established from primary tumors or metastases expressed OX1R mRNA and underwent important apoptosis on orexin-A challenge. Most interestingly, orexin-A also promoted robust apoptosis in cells that are resistant to the most commonly used drug in colon cancer chemotherapy, 5-fluorouracil. When human colon cancer cells were xenografted in nude mice, orexin-A administered at day 0 strongly slowed the tumor growth and even reversed the development of established tumors when administered 7 days after cell inoculation. Orexin-A also acts by promoting tumor apoptosis in vivo because caspase-3 is activated in tumors on orexin treatment of nude mice. These findings support that OX1R is an Achilles heel of colon cancers, even after metastasis or chemoresistance. They suggest that OX1R agonists might be novel candidates for colon cancer therapy. Cancer Res; 71(9);

Heteromultimerization of Cannabinoid CB1 Receptor and Orexin OX1 Receptor Generates a Unique Complex in Which Both Protomers Are Regulated by Orexin A

“…Polypeptides with apparent mass labeled (i-iv) in A were quantitated in B across lanes 1-10. because of this, the current studies have been limited to using the native peptide agonist orexin A as an activator of the OX 1 receptor. This may change with indications that agonists at the OX 1 receptor could be effective in the treatment of colon cancer (63,64). The CB 1 receptor has been a target of great interest not least because of the psychotropic effects of the active ingredient of cannabis produced via activation of this receptor.…”

The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases

“…In general terms, when proliferation of malignant tumors is offset by similar rates of apoptosis, the tendency to develop a malignancy is reduced, while an impairment in the degree of apoptosis and a corresponding increase in proliferation favors the development of intestinal malignancy [110,111]. In a recent study, Voisin et al [112] showed that re-establishing the balance between apoptosis and proliferation within tumors through the stimulation of OX1R, a proapoptotic transmembrane receptor, was sufficient to slow tumor growth and prevent new tumor formation. Furthermore, several studies have found that deficiencies in the apoptotic mechanism can also result from abnormalities or mutations in important homeostatic proteins such as p53, K-ras, APC, EGF-R, and TLRs [1,[113][114][115], and some of these mutations may serve to be informative biomarkers of disease.…”

GPCRs and cancer

“…In addition, an aberrant activation of GPCRs by high levels of ligands like LPA, S1P and chemokines was involved in cell transformation, proliferation, angiogenesis, metastasis and drug resistance [6] . Conversely, some members of GPCRs, such as the orexin receptor OX1R, were shown to mediate a pro-apoptotic action in various cancer cells [8] .…”