Klotho suppresses colorectal cancer through modulation of the unfolded protein response

Abstract

Klotho is an anti-aging transmembrane protein, which can be shed and function as a hormone. Accumulating data indicate klotho as a tumor suppressor in a wide array of malignancies and indicate the subdomain KL1 as the active region of the protein. We aimed to study the role of klotho as a tumor suppressor in colorectal cancer. Bioinformatics analyses of TCGA datasets indicated reduced klotho mRNA levels in human colorectal cancer, along with negative regulation of klotho expression by hypermethylation of the promoter and 1st exon, and hypomethylation of an area within the gene. Overexpression or treatment with klotho or KL1 inhibited proliferation of colorectal cancer cells in vitro. The in vivo activity of klotho and KL1 was examined using two models recapitulating development of tumors in the normal colonic environment of immune-competent mice. Treatment with klotho inhibited formation of colon polyps induced by the carcinogen azoxymethane, and KL1 treatment slowed growth of orthotopically-implanted colorectal tumors. Gene expression array revealed that klotho and KL1 expression enhanced the unfolded protein response (UPR) and this was further established by increased levels of spliced XBP1, GRP78 and phosphorylated-eIF2α. Furthermore, attenuation of the UPR partially abrogated klotho tumor suppressor activity. In conclusion, this study indicates klotho as a tumor suppressor in colorectal cancer and identifies, for the first time, the UPR as a pathway mediating klotho activities in cancer. These data suggest that administration of exogenous klotho or KL1 may serve as a novel strategy for prevention and treatment of colorectal cancer.

Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes

“…They reported that klotho downregulation significantly increases ER stress and activation of UPR signaling upon treatment with agents disrupting ER homeostasis by affecting ER Ca 2+ pump and N-linked glycosylation of proteins [12]. Ameliorating effect of klotho on ER stress and its role in modulation of the unfolded protein response was described also in some other studies [13][14][15]. Moreover, the role of klotho in LPS-mediated ER stress was studied in a different cell model.…”

Klotho‐mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments

“…The studies described above have suggested that senescent stromal cells may help promote the malignant behavior of CRC cells. Klotho, a widely recognized anti‐aging protein, was previously proposed to act as a tumor suppressor in CRC (Arbel Rubinstein et al ., ; Pan et al ., ). Pretreatment of the senescent WI‐38 with Klotho partially reversed the enhanced proliferation and invasion seen after treating the CRC lines with senescent WI‐38 CM.…”

Klotho and the Treatment of Human Malignancies

“…The analyses of publicly available DNA methylation datasets revealed a specific site in the first exon of KLOTHO, within a CpG island, that is hypermethylated in human colorectal cancer. Hypermethylation of the first exon, as well as promoter hypermethylation, negatively regulated Klotho expression in colorectal cancer [69]. This group demonstrated that overexpression using HA-tagged Klotho via transfection resulted in a reduction of surviving cancer colonies by at least 85% in colorectal HCT-116 and HT-29 cells.…”

“…The investigators tested the effects of Klotho in vivo on either chemically induced carcinogenic, or orthotopic mouse models in which MC38 colorectal cancer cells were injected into the colonic submucosa. Mice treated with soluble Klotho exhibited significantly reduced weight and volume of the orthotopic tumour [69]. Furthermore, Klotho has been shown to be down-regulated through promoter methylation in 83.3% of colon cancer cell lines and 85% of primary colorectal cancer tissues [45].…”

“…Cell lines HCT116, H-29, SW480, Colo-320 [69] Orthotopic C57BL/6 mice using MC38 colorectal cancer cells [69] Azoxymethane induced polyps in C57BL/6 immune-competent mice [44] Decreased Klotho expression in colon cancer tissues [45] Oesophageal and Gastric Cancer…”