Lipocalin 2 inversely regulates TRAIL sensitivity through p38 MAPK-mediated DR5 regulation in colorectal cancer

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs)4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. In this study, we provide evidence demonstrating the role of lipocalin 2 (LCN2) in the TRAIL-mediated apoptosis of human colorectal cancer (CRC). By analyzing the mRNA expression data of 71 CRC tissues from patients, we found that DR5 was preferentially expressed in CRC tissues with a low LCN2 expression level compared to tissues with a high LCN2 expression level. Moreover, we analyzed the association between DR5 and LCN2 expression and this analysis revealed that DR5 expression in CRC tended to be inversely associated with LCN2 expression. By contrast, no association was found between the DR4 and LCN2 expression levels. The expression patterns of LCN2 in human CRC cell lines also exhibited an inverse association with DR5 expression. The knockdown of LCN2 by siRNA in the TRAIL‑resistant CRC cells expressing high levels of LCN2 led to a significant increase in TRAIL-induced apoptosis through the upregulation of DR5 protein and mRNA expression. The mechanism through which LCN2 silencing sensitized the CRC cells to TRAIL was dependent on the extrinsic pathway of apoptosis. In addition, we identified that the knockdown of LCN2 enhanced the sensitivity of the cells to TRAIL through the p38 MAPK/CHOP-dependent upregulation of DR5. Taken together, the findings of this study suggest that LCN2 is responsible for TRAIL sensitivity and LCN2 may thus prove to be a promising target protein in DR-targeted CRC therapy.

In vitroandin vivoevidences propound therapeutic potential of Lipocalin 2 in cervical carcinoma

“…In this study, inhibiting LCN2 using anti-LCN2 antibody resulted in suppression of major tumor promoting signalling pathways like TNF alpha, IL17 and NFkB signalling, which ultimately resulted in tumor regression. Numerous reports suggest that all these pathways are linked to LCN2 in various human malignancies [55][56][57][58][59] . For example, in PC-3 prostate cancer cells, it has been reported that TNF alpha stimulates LCN2, thus protecting the tumor cells from apoptotic cell death.…”

Increased expression of LCN2 formed a positive feedback loop with activation of the ERK pathway in human kidney cells during kidney stone formation

“…In view of the molecular mechanism of the formation of kidney stones, studies have shown that LCN2 may play an important role 16 . LCN2, which is also known as neutrophil gelatinase-associated LCN, is expressed in tubular cells and neutrophils and is related to cellular apoptosis and inflammation 17,18 . However, little is known about the role of LCN2 in kidney stones.…”

“…However, little is known about the role of LCN2 in kidney stones. There are also studies that indicate that LCN2 can be regulated and that it is associated with many signalling pathways in certain tumour cell models [10][11][12][13][14][15][16][17][18][19] . However, little is known about the specific regulation of LCN2 and the role of LCN2 and related signalling pathways in kidney stones.…”

Another Weapon against Cancer and Metastasis: Physical-Activity-Dependent Effects on Adiposity and Adipokines

“…LCN2 is involved in TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in CRC. The mRNA expression data for 71 CRC tissues have revealed that the expression of TRAIL-R2 is inversely related to LCN2 and LCN2 knockdown in CRC cells, which increases the sensitivity to TRAIL via p38 MAPK/CHOP-induced upregulation of TRAIL-R2 [138].…”