Abstract
Lung cancer is recognized as a major cause of mortality worldwide owing to its metastatic activity. Given the lack of solid information regarding the possible effects of caffeine, one of the most consumed natural psychoactive substances, on molecular signaling pathways implicated in the aggressive behavior of lung cancer, our study aimed to evaluate the effect and mechanism of caffeine on metastasis-related mechanisms. The results revealed that caffeine treatment at concentrations of 0–500 µM caused no direct cytotoxic effects on NCI-H23 cells. Treatment of cells with caffeine showed good potential to inhibit cell proliferation at 48 h and induced significant cell cycle arrest at the G0/G1 phase. Concerning metastasis, caffeine was shown to reduce filopodia formation, inhibit migration and invasion capability, and reduce the ability of cancer cells to survive and grow in an anchorage-independent manner. Moreover, caffeine could attenuate the formation of 3D tumor spheroids in cancer stem cell (CSC)-enriched populations. With regard to mechanisms, we found that caffeine significantly altered the integrin pattern of the treated cells and caused the downregulation of metastasis-associated integrins, namely, integrins αv and β3. Subsequently, the downstream signals, including protein signaling and transcription factors, namely, phosphorylated focal adhesion kinase (p-FAK), phosphorylated protein kinase B (p-Akt), cell division cycle 42 (Cdc42), and c-Myc, were significantly decreased in caffeine-exposed cells. Taken together, our novel data on caffeine-inhibiting mechanism in relation to metastasis in lung cancer could provide insights into the impact of caffeine intake on human diseases and conditions.
Highlights
This article is an open access articleHuman lung cancer has been identified as one of the most critical types of cancers, accounting for nearly one in five of all cancer-related deaths worldwide [1]
To assess the effects of caffeine on the metastasis regulatory mechanism of human To assess the effects of caffeine on the metastasis regulatory mechanism of human lung cancer cells, we first investigated non-toxic concentrations of caffeine
The cells were treated with caffeine at various concentrations (0–500 μM) for 24, 48, and 72 h, and cell treated with caffeine at various concentrations (0–500 μM) for 24, 48, and 72 h, and cell viability was evaluated by MTT assay
Summary
This article is an open access articleHuman lung cancer has been identified as one of the most critical types of cancers, accounting for nearly one in five of all cancer-related deaths worldwide [1]. The prevention of cancer metastasis via inhibition of associated mechanisms may be a way to improve the survival and prognosis of lung cancer patients. Cells induce actin polymerization which leads to an extension of cell protrusions together with the creation of new cell–extracellular matrix (ECM) adhesions through FA formation at the leading edge of cells. These processes result in the generation of the mechanical force that helps cells to move forward. It has been reported that heterodimers of integrin α5β1 and αvβ could promote EGF receptor signaling and invasion of lung cancer [13]
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