Abstract
Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.
Highlights
Cancer is a major cause of morbidity and mortality worldwide [1]
This review aims to describe the pathways involved in hypoxia-induced cancer development and more importantly explain how melatonin can possibly inhibit hypoxia-mediated tumor progression
Hypoxia leads to the detachment of tumor cells by downregulating cell adhesion molecules, and by up-regulating the molecules involved in the degradation of integrin and cell attachment components such as matrix metalloproteinases (MMPs)-9 and urokinasetype plasminogen activator receptor [48,49]
Summary
Cancer is a major cause of morbidity and mortality worldwide [1]. genetic mutations have a decisive role in cancer development, many cancers are a consequence of environmental risk factors such as diet, smoking, pollutants, stress, inflammation, etc. [2]. Several features of cancer cells pave the way for tumor development, including persistent proliferation and insensitivity to growth suppressors, constant DNA replication, evasion of both apoptosis and immune surveillance, impaired energy metabolism, sustained angiogenesis, invasion, and metastasis [3]. Hypoxia (oxygen tension less than 7 mmHg), which is sensed by hypoxia-inducible factors (HIFs), induces overexpression of the growth factors and cellular adaptation genes which subsequently promote angiogenesis, cancer cell survival, proliferation, and energy metabolism [6]. Hypoxia negatively affects tumor proliferation in some conditions, it mainly allows tumor cells to adapt to insufficient oxygen and nutrients and enhances the activity and aggressiveness of cancer cells. Hypoxia affects the metabolic pathways to proup-regulation of ECM degradation molecules such as MMP-9 and urokinase-type plasminogen vide high energy for cancer cells by (1) enhancing the transcription of glucose transporters genes activator receptor (uPAR). 1 (GBE1), reducing and -3). phosphorylase (GP) activity, and (4) diverting pyruvate from the citric acid cycle into lactate glycogen by pyruvate dehydrogenase kinases-1 and -3 (PDK-1 and -3)
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