Abstract
The orexin-A and its receptors are associated with many physiological processes in peripheral organs and the central nervous system and play important roles in a series of human diseases, including narcolepsy, obesity, and drug addiction. Increasing evidence has indicated high expression of orexin-A and OX1 receptor (OX1R) in malignant tumors, suggesting that the stimulation of OX1R might be essential for tumorigenesis. Here, we attempted to clarify the correlation between orexin-A expression and malignancy in pancreatic cancer. Our results indicated that the stimulation of OX1R promotes cell proliferation in pancreatic cancer PANC1 cells. Additionally, orexin-A treatment can protect PANC1 cells from apoptosis, whereas inhibition of the stimulation of OX1R results in apoptosis through regulating pancreatic cancer cell expression levels of Bcl-2, caspase-9, and c-myc, which are key apoptotic factors. Further investigation revealed that orexin-A treatment activates theAkt/mTOR signaling pathway to promote cell proliferation byinhibiting Bcl-2/caspase-9/c-myc-mediated apoptosis in pancreatic cancer cells. Our findings revealed that the stimulation of OX1R might be important for tumorigenesis in pancreatic cancer and is a potential target for the treatment of patients with pancreatic cancer.
Highlights
Pancreatic cancer (PC), a relatively rare but highly lethal malignancy, is projected to be the third most deadly cancer, and 53,670 estimated cases and 43,090 deaths occurred in the United States in 2017 [1]
Our findings provide insight into the mechanisms by which orexin-A/OX1 receptor (OX1R) contributes to cell proliferation and apoptosis, which might be helpful for clinical therapy for patients with pancreatic cancer
Our results indicated that SB408124 treatment, which subsequently resulted in the inhibition of stimulation of OX1R, induced cell apoptosis in PANC1 cells (Figures 4A,B, right panel, red arrow), whereas cell apoptosis was almost undetectable in orexin-A-treated or nontreated PANC1 cells (Figures 4A,B, left and middle panels, red arrow), suggesting that the regulation of the stimulation of OX1R may be involved in cell apoptosis in pancreatic cancer cells
Summary
Pancreatic cancer (PC), a relatively rare but highly lethal malignancy, is projected to be the third most deadly cancer, and 53,670 estimated cases and 43,090 deaths occurred in the United States in 2017 [1]. The poor prognosis related to pancreatic cancer is due to delayed diagnosis because over 90% of patients with pancreatic cancer are diagnosed at stages III or IV [2]. The identification of novel biomarkers responsible for the progression of pancreatic cancer might be required for the prevention, early diagnosis and improved systemic therapy of pancreatic cancer. The functions of orexin peptides are mediated via interaction with two G-proteincoupled receptors (GPCRs), orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) [4, 14, 15]. In addition to the hypothalamus, orexins and their receptors are widely distributed throughout peripheral tissues, including adipose, gut, pancreatic, adrenal gland and testis tissues [16,17,18]
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