Abstract
Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.
Highlights
Lung cancer (LC) is the most common and deadly cancer that has recorded 2.2 and 1.8 million new cases and deaths, respectively, in 2020 worldwide[1]
The enhanced stability of hypoxicinduced factor-1α (HIF-1α) increases the expression of C–X–C chemokine receptor type 4 (CXCR4) and erythropoietin EPO, which are the main regulators of metastasis and angiogenesis in cancer[8,9]
We demonstrated that CPM inhibits APEX1/hypoxic-induced factor (HIF)-1α interaction, as well as their targeted hypoxia-induced genes including carbonic anhydrase 9 (CA9), CXCR4, and EPO, which leads to the inhibition of intracellular reactive oxygen species (ROS), pH, migration, and angiogenesis of hypoxic LC cells
Summary
Lung cancer (LC) is the most common and deadly cancer that has recorded 2.2 and 1.8 million new cases and deaths, respectively, in 2020 worldwide[1]. LC occurs due to the epigenetic and molecular deformities[2]. Hypoxia plays a major role in the microenvironment of solid tumors. Intra-tumoral hypoxia has been associated with malignant phenotypes and poor prognosis, as well as with chemo- and radiotherapy resistance[3]. The main mediators of biological response to hypoxia. Carbonic anhydrase 9 (CA9) as one of the key target genes activated by HIF-1α can neutralize intracellular acidosis[7]. The enhanced stability of HIF-1α increases the expression of C–X–C chemokine receptor type 4 (CXCR4) and erythropoietin EPO, which are the main regulators of metastasis and angiogenesis in cancer[8,9]. HIF-1α is a vital transcriptional mediator that plays an important role in the alteration of tumor cells in Official journal of the Cell Death Differentiation Association
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