ELA/APELA precursor cleaved by furin displays tumor suppressor function in renal cell carcinoma through mTORC1 activation

Abstract

Renal cell carcinoma (RCC) is one of the most common malignancies worldwide, accounting for 140,000 cancer-related deaths and 330,000 new cases a year (1). Various environmental and daily life risk factors for RCC are well established, including hypertension, obesity, and several chronic kidney diseases. In adults, malignant kidney tumors mainly arise from the renal parenchyma and renal pelvis (2). RCC is classified into clear cell RCC (ccRCC), papillary RCC, and chromophobe RCC subtypes (2). Accounting for up to 75% of all RCCs, ccRCC is predominantly sporadic, and only 5% of ccRCC cases are associated with hereditary syndromes (von Hippel-Lindau disease) (2). Up to 50% of renal cancer patients develop metastatic disease, which remains incurable, and the median survival time is less than 28 months (3). Successful treatment procedures are currently limited because of the lack of thorough understanding of the basic molecular pathways involved in RCC carcinogenesis and lack of genetically pertinent animal models (4). Currently, signaling pathways that promote RCC metastatic progression are the subject of various studies, and tyrosine kinases have emerged as important determinants of RCC neoplasia (3-5). The apelin peptides and their cognate G protein-coupled receptor (GPCR) known as the apelin receptor (Aplnr) play a key role in apoptosis, cell proliferation, angiogenesis, metabolic disorders, and various cancers (6, 7). After Aplnr activation, a wide range of signaling pathways mediate these biological processes. These signaling pathways include phosphorylation of protein kinase B (AKT), ERK1/2 (8), calcium mobilization (8, 9), cAMP (6), and NOS (10). Previously, 2 groups separately identified Elabela (ELA) (11, 12) as a new Apelin is a well-established mediator of survival and mitogenic signaling through the apelin receptor (Aplnr) and has been implicated in various cancers; however, little is known regarding Elabela (ELA/APELA) signaling, also mediated by Aplnr, and its role and the role of the conversion of its precursor proELA into mature ELA in cancer are unknown. Here, we identified a function of mTORC1 signaling as an essential mediator of ELA that repressed kidney tumor cell growth, migration, and survival. Moreover, sunitinib and ELA showed a synergistic effect in repressing tumor growth and angiogenesis in mice. The use of site-directed mutagenesis and pharmacological experiments provided evidence that the alteration of the cleavage site of proELA by furin induced improved ELA antitumorigenic activity. Finally, a cohort of tumors and public data sets revealed that ELA was only repressed in the main human kidney cancer subtypes, namely clear cell, papillary, and chromophobe renal cell carcinoma. Aplnr was expressed by various kidney cells, whereas ELA was generally expressed by epithelial cells. Collectively, these results showed the tumorsuppressive role of mTORC1 signaling mediated by ELA and established the potential use of ELA or derivatives in kidney cancer treatment.

Furin Prodomain ppFurin Enhances Ca2+ Entry Through Orai and TRPC6 Channels’ Activation in Breast Cancer Cells

“…An increasing number of studies have identified a wide range of protein precursors in breast cancer cells of which the cleavage and activity are inhibited by furin repression [ 10 , 17 , 31 , 33 , 52 ]. These studies highlight the important role for the cleavage of these protein precursors in breast cancer development and progression and reveal that their cleavage inhibition results in tumor cells proliferation, invasion, and survival inhibition.…”

“…The wound-healing assay was conducted as previously reported [ 52 ]. Briefly, control and ppFurin-expressing cells were seeded into 6-well plates at 5 × 105/well and grown in growth media until 90–100% confluency.…”

Loss of Proprotein Convertase Furin in Mammary Gland Impairs proIGF1R and proIR Processing and Suppresses Tumorigenesis in Triple Negative Breast Cancer

“…Furin has been implicated in regulating multiple oncogenic pathways like MAPK and PI3K signaling [ 11 , 50 ]. Our finding here supports the idea that inhibition of MAPK and PI3K signaling by interfering with maturation of proIGF1R and proIR contributes to inhibiting tumor growth by enhancing apoptosis in the PyMT-induced TNBC mouse model ( Figure 4 C,D).…”

Study Progression of Apelin/APJ Signaling and Apela in Different Types of Cancer

“…Recent years saw a significant increase in the studies focusing on the association between Apela and cancer. Soulet et al found that Apela was usually expressed by epithelial cells while expression of APJ could be found in various kidney cells (77). Expression of Aplea was reduced in the main kidney cancer subtypes, namely, clear cell, papillary, and chromophobe RCC.…”