Apelin/APJ signaling activates autophagy to promote human lung adenocarcinoma cell migration☆
Graphical abstract
Introduction
Apelin, the endogenous ligand of APJ [1], was isolated from the bovine stomach in 1998 [2]. Apelin isoforms have at least four bioactive forms including apelin-12, -13, -17, and -36. Researchers have confirmed that apelin and APJ exist in a variety of tissues such as heart, lung, brain, kidney, liver, blood vessels, and apelin/APJ system involved in a wide range of physiological and pathological functions [3], [4]. Apelin is reported as an oncogene in many cancer including lung cancer [5], breast cancer [6], prostate cancer [7], gastric cancer [8], oral cancer [9], colon cancer [10], ovarian cancer [11] and glioblastoma [12]. It plays important roles in carcinogenesis and tumor progress by inducing angiogenesis, metastasis, and therapy resistance [13].
In lung cancer, apelin significantly stimulates non-small cell lung cancer growth and micro-vessel formation [14]. Our previous research reveals that apelin/APJ promotes lung adenocarcinoma cell proliferation [15] and migration [16]. However, the intracellular mechanisms of apelin-regulated lung adenocarcinoma cell migration are not clear.
Autophagy is a conservative intracellular process in different species [17]. Recent studies discover that autophagy played major role in human cancer progression. Numerous studies demonstrate that autophagy promotes cancer cell proliferation and inhibits cancer cell apoptosis [18], [19], [20]. Autophagy is considered to play an important role in cancer cell migration [21], [22], [23], [24]. In lung cancer, researchers have verified that autophagy promotes cell migration [25]. However, it is unclear how autophagy controls migration. What's more, the upstream pathway that controls autophagy activation in lung cancer remains unclear.
Apelin plays inverse roles in autophagy reported in present studies. Apelin inhibited glucose deprivation-induced autophagy in rat cardiomyocytes [26] and hypoxia-induced autophagy in pulmonary arterial smooth muscle cells [27]. Apelin was involved in progression of diabetic nephropathy by inhibiting autophagy [28]. However, we found that the ROS-autophagy pathway mediates monocytes-human umbilical vein endothelial cells adhesion induced by apelin-13 [29]. The autophagy pathway is involved in apelin-13-induced cardiomyocyte hypertrophy [30], [31]. Additionally, over-expressed apelin/APJ activated autophagy in cancer. In lung adenocarcinoma, our previous research has revealed that apelin secretion in plasma and APJ expression in tissue of lung adenocarcinoma patients was increased. We also have proved that both over-expressed apelin and APJ increased BECN1 expression in A549 cells, revealing that apelin and APJ may activate autophagy in lung adenocarcinoma [15]. Therefore, we hypothesize that apelin promotes autophagy to induce migration in lung adenocarcinoma. Given the important role of autophagy, we focus on autophagy in therapeutic targeting.
Section snippets
Cell culture
Lung cancer A549 cells, H1299 cells, Human HEK293T were purchased from American Type Culture Collection (ATCC). A549 and H1299 cell lines that overexpress exogenous APJ or knockdown BECN1 were established as the below description. Cells were cultured in RPMI-1640 (GIBCO), supplemented with 10% FBS (GIBCO). Cells were kept in a 37 °C, 5% CO2-water jacket (Thermo scientific). A549 and H1299 cell lines were also recently authenticated using a STR DNA fingerprinting at Shanghai Biowing Applied
Autophagy-related genes are highly expressed in lung adenocarcinoma
Studies indicate that autophagy plays crucial roles in tumorigenesis and tumor progression including metastasis [35], [36]. To reveal autophagy activation in lung adenocarcinoma, firstly, we investigated the change of autophagy-related gene expression in lung adenocarcinoma. We downloaded a lung adenocarcinoma microarray dataset, GSE 2514 [37], and assessed the expression of autophagy-related genes including ATG5, ATG9, et al. As shown in Fig. 1A, autophagy-related gene expression was entirely
Discussion
Presently researches implied that apelin/APJ was a novel cancer factor [44]. Evidence confirmed that apelin/APJ played key roles in cancer cell migration [45], [46]. However, the underlying mechanisms keep major unclear. What's more, apelin has conflicting roles in autophagy. Here, we demonstrate that apelin induces autophagy activation in lung adenocarcinoma which dependents on its endogenous receptor APJ. Apelin/APJ activates autophagy by promoting Beclin1 expression via HIF1A. In our
Conclusion
In summary, we report a novel link in which the connection between G protein-coupled receptor APJ and autophagy in lung adenocarcinoma which connected to cell metastasis. We also reveal a novel mechanism that apelin increases cofilin phosphorylation in autophagy dependent manner (Fig. 7). Targeting autophagy is a potential strategy for lung adenocarcinoma therapy.
CRediT authorship contribution statement
Conception and design: Deguan Lv, Lanfang Li, Cuiqing Zhong, and Linxi Chen.
Acquisition of data (acquired patients, provided facilities, etc.): Deguan Lv, Jiaqi Liu, Zhe Chen, Xuling Luo, and Li Yang.
Analysis and interpretation of data (e.g. statistical analysis, biostatistics, computational analysis): Deguan Lv, Xuling, Zhe Chen, Meiqing Liu, Yao Li, Shifang Huang, and Feng Xie.
Writing, reviewing, and/or revision of the manuscript: Deguan Lv, Zhe Chen, Cuiqing Zhong, Linxi Chen, Mingzhu. Tang,
Declaration of competing interest
All authors have completed the ICMJE uniform disclosure form. The authors have no conflicts of interest to declare.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81703515, 81670265, and 81503074). This work was also supported in part by Initiative Postdocs Supporting Program (BX201600108 to Cuiqing Zhong).
References (52)
- et al.
A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11
Gene
(1993) - et al.
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor
Biochem. Biophys. Res. Commun.
(1998) - et al.
Hypoxia-induced up-regulation of apelin is associated with a poor prognosis in oral squamous cell carcinoma patients
Oral Oncol.
(2012) - et al.
Apelin/APJ system and cancer
Clin. Chim. Acta
(2016) - et al.
Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis
J. Thorac. Oncol.
(2010) - et al.
Autophagy modulates transforming growth factor beta 1 induced epithelial to mesenchymal transition in non-small cell lung cancer cells
Biochim. Biophys. Acta
(2018) - et al.
Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/beta-catenin signaling pathway activation in hepatocellular carcinoma cells
J. Exp. Clin. Cancer Res.
(2018) - et al.
Autophagy modulates transforming growth factor beta 1 induced epithelial to mesenchymal transition in non-small cell lung cancer cells
Biochim. Biophys. Acta Mol. Cell Res.
(2018) - et al.
Autophagy induced by overexpression of DCTPP1 promotes tumor progression and predicts poor clinical outcome in prostate cancer
Int. J. Biol. Macromol.
(2018) - et al.
p62 in cancer: signaling adaptor beyond autophagy
Cell
(2016)
APJ regulates parallel alignment of arteries and veins in the skin
Dev. Cell
Ginkgolide K promotes astrocyte proliferation and migration after oxygen-glucose deprivation via inducing protective autophagy through the AMPK/mTOR/ULK1 signaling pathway
Eur. J. Pharmacol.
LncRNA DICER1-AS1 promotes the proliferation, invasion and autophagy of osteosarcoma cells via miR-30b/ATG5
Biomed. Pharmacother.
Dysregulated microRNA-224/apelin axis associated with aggressive progression and poor prognosis in patients with prostate cancer
Hum. Pathol.
Accessories to the crime: functions of cells recruited to the tumor microenvironment
Cancer Cell.
Apelin/APJ system: an emerging therapeutic target for respiratory diseases
Cell. Mol. Life Sci.
Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis
Acta Biochim. Biophys. Sin. Shanghai
Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy
EMBO Mol. Med.
Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients
Sci. Rep.
Mechanisms of tumor-lymphatic interactions in invasive breast and prostate carcinoma
Int. J. Mol. Sci.
circ-NOTCH1 acts as a sponge of miR-637 and affects the expression of its target gene Apelin to regulate gastric cancer cell growth
Biochem. Cell Biol.
The role of apelin and apelin receptor expression in migration and invasiveness of colon cancer cells
Anticancer Res.
Apelin abrogates the stimulatory effects of 17beta-estradiol and insulin-like growth factor-1 on proliferation of epithelial and granulosa ovarian cancer cell lines via crosstalk between APLNR and ERalpha/IGF1R
Mol. Biol. Rep.
Apelin controls angiogenesis-dependent glioblastoma growth
Int. J. Mol. Sci.
ERK1/2 mediates lung adenocarcinoma cell proliferation and autophagy induced by apelin-13
Acta Biochim. Biophys. Sin. Shanghai
PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13
Clin. Exp. Pharmacol. Physiol.
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The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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Deguan Lv, Xuling Luo and Zhe Chen all contribute equally to this study.