Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, β‐catenin, and Twist pathways

Abstract

Lung cancer is one of the most common cancer in cancer-related deaths worldwide, which is characterized by its strong metastatic potential. The melatonin hormone secreted by the pineal grand has an antioxidant effect and protects cells against carcinogenic substances. However, the effects of melatonin in lung cancer stemness are largely unknown. We found that melatonin reduces CD133 expression by~50% in lung cancer cell lines, while results of a sphere formation assay showed that melatonin inhibits lung cancer stemness. These effects of melatonin were reversed when the cell lines were incubated with phospholipase C (PLC), ERK/p38, and a β-catenin activator. Transfection with Twist siRNA augmented the inhibitory effects of melatonin, indicating that melatonin suppresses lung cancer stemness by inhibiting the PLC, ERK/p38, β-catenin, and Twist signaling pathways. We also found CD133 expression is positively correlated with Twist expression in lung cancer specimens. Melatonin shows promise in the treatment of lung cancer stemness and deserves further study. K E Y W O R D S lung cancer, melatonin, stemness, Twist 1 | INTRODUCTION Lung cancer is a major occasion of cancer mortality. Non-small cell lung cancer (NSCLC) is the most general type of lung cancer, accounting for more than 85% of all lung cancers. 1,2 Although chemotherapy and radiotherapy have improved lung cancer treatment over the past few decades, survival rates remain poor, with approximately 15% of patients remaining alive at 5 years after diagnosis. This poor prognosis is due to metastasis in the late stage of disease. Cells with a stem-like, dormant phenotype, endowed with unlimited self-renewal and high tumorigenic capability, are deemed responsible for post-therapy relapse and metastatic dissemination in various cancers, including lung cancer. 3-5 Therefore, the drugs that attack the cancer stem cells (CSCs) population have therapeutic benefit.Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal grand and other organs, is produced in a circadian rhythm in reply to photic signaling from the retina. 6,7 Melatonin is important for controlling the immune system 8-10 and has an antioxidant effect. 11,12 This agent protects cells against carcinogenic substances and inhibits the development, metastasis, invasion and angiogenesis of many types

Dioscorea nipponica Makino suppresses TPA‐induced migration and invasion through inhibition of matrix metalloproteinase‐9 in human cervical cancer cells

“…29,35,36 The involvement of the MAPK pathway across different malignancies was also proposed. [37][38][39][40] Furthermore, mutations implicating the MAPK/ERK pathway identified in human cancers have the potential for targeting. 38 The underlying mechanisms of several compounds in cervical cancer cells have been reported.…”

Contribution of GPD2/mGPDH to an alternative respiratory chain of the mitochondrial energy metabolism and the stemness in CD133‐positive HuH‐7 cells

“…As a downstream factor of CD133’s signal transduction, we found that p38 is involved specifically in the G3P‐driven ATP synthesis activity by GPD2. As for p38, it has been reported that p38 activity and the expression of CD133 may have correlation in cancer stem cells originating from lung cancer, melanoma and liver cancer (Erdogan et al, ; Kumar et al, ; Wang et al, ; Yang et al, ; Zhao, Jia, Han, & Zhang, ). Furthermore, it has been shown that inhibition of p38 kinase activity suppressed cancer stem cell characteristics such as migration, infiltration and anchorage‐independent growth (Lee et al, ).…”

“…**p < .01 with one-sample t-test (f) ATP synthesis activity by GPD2. As for p38, it has been reported that p38 activity and the expression of CD133 may have correlation in cancer stem cells originating from lung cancer, melanoma and liver cancer (Erdogan et al, 2018;Kumar et al, 2016;Wang et al, 2015;Yang et al, 2019;Zhao, Jia, Han, & Zhang, 2018). Furthermore, it has been shown that inhibition…”

Resistin enhances IL‐1β and TNF‐α expression in human osteoarthritis synovial fibroblasts by inhibiting miR‐149 expression via the MEK and ERK pathways

“…OASFs were co‐transfected with 1 μg plasmid and 0.4 μg β‐galactosidase expression vector, then dispersed over the 12‐well plates and lysed with reporter lysis buffer 24 hours after transfection. The Dual‐Luciferase Reporter Assay System was used to determine the extent of luciferase and Renilla activities in the cellular extracts, and relative luciferase activity was quantified by the ratio of luciferase/Renilla activity referenced to the ratio of control samples 1,19,20 …”