Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells

Shu, Guoshun; Xie, Biao; Ren, Feng; Liu, Dongcai; Zhou, Jun; Li, Qinglong; Chen, Jinhui; Yuan, Long; Zhou, Jianping

doi:10.1007/s13402-012-0118-0

Cited by 59 publications

(45 citation statements)

References 27 publications

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“…IGF1R simulates colon cancer cell growth via activation of the PI3K/AKT pathway (29). Our present study also demonstrated that overexpression of KL could downregulate the expression of IGF1R, p-PI3K and p-AKT in colon cancer cells, suggesting that KL might regulate IGF1R and subsequently activate the downstream PI3K/Akt signaling pathway (23,25).…”

Section: Discussionsupporting

confidence: 72%

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Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

Huang

Peng

et al. 2014

International Journal of Oncology

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Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers including colon cancer. However, the potential role and molecular events for KL in colon cancer remain unclear. The present study aimed to investigate the expression of KL in human colon cancer by immunohistochemistry, and to analyze the correlation between KL expression and clinicopathological characteristics of patients with colon cancer. Functional analysis after lentivirus-mediated gain of KL expression was used to assess the tumor growth and invasion in colon cancer cells in vitro and in vivo. The rate of KL expression was significantly decreased in cancer tissues compared with that in adjacent non-cancer tissues (ANCT) (60.3 vs.77.9%, P=0.022), and KL expression was negatively associated with Dukes staging (P=0.034) and depth of tumor invasion (P=0.008). Overexpression of KL in vitro inhibited cell proliferative activities and invasive potential in colon cancer cells, companied with decreased expression of p-IGF1R, p-PI3K, p-AKT, PCNA and MMP-2. In addition, the tumor volumes in the HT-29 subcutaneous tumor model treated with lentivirus‑mediated KL vector (Lv-KL) was significantly smaller than those of the negative control (NC) group (P<0.01). Taken together, our findings indicate that the expression of KL is downregulated in human colon caner and correlates with tumor invasion and Dukes staging, while overexpression of KL suppresses growth and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells, suggesting that KL may serve as a potential therapeutic target for the treatment of colon cancer.

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Section: Discussionsupporting

confidence: 72%

“…Exogenous KL gene expression significantly inhibits cell growth and invasion, and induces cell apoptosis and autophagy in HCC (23)(24)(25). Inversely, some studies have revealed a novel oncogenic function of KL of in promoting tumor migration and invasion via activation of VEGFR2/PAK1 signaling (26).…”

Section: Discussionmentioning

confidence: 99%

Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

Huang

Peng

et al. 2014

International Journal of Oncology

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“…Xie et al (36) measured mRNA and protein expression levels of α-Klotho in 64 HCC tumor tissues using real-time polymerase chain reaction and immunohistochemistry, respectively, demonstrating that a loss of α-Klotho expression in HCC cells was a predictive factor for the poor prognosis of the disease. Similarly, Shu et al (37) reported that exogenous expression of the Klotho gene significantly inhibited the proliferation of HCC cells, induced HCC cell apoptosis and decreased HCC cell migration, using a Matrigel invasion chamber assay. Conversely, following the analysis of 52 hepatoma patients, Chen et al (38) reported that immunohistochemical α-Klotho staining was significantly associated with liver cirrhosis, tumor multiplicity and venous invasion, and the survival rate of subjects with high α-Klotho expression was significantly decreased compared to patients with low α-Klotho expression.…”

Section: Discussionmentioning

confidence: 91%

Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis

Prystupa¹,

Dabrowska²,

Sak³

et al. 2016

Experimental and Therapeutic Medicine

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The aim of the present study was to evaluate the concentrations of fetuin-A, osteoprotegerin (OPG) and α-Klotho protein in patients with alcoholic cirrhosis at different stages of the disease, and to demonstrate that fetuin-A, osteoprotegin and α-Klotho may be used as markers of the severity of cirrhosis. A total of 54 patients with alcoholic liver cirrhosis treated in various hospitals in the Lublin region of Poland were randomly enrolled. The control group consisted of 18 healthy individuals without liver disease, who did not drink alcohol. Serum levels of fetuin-A, OPG and α-Klotho were measured by ELISA kits. Levels of fetuin-A were significantly reduced in patients with alcoholic liver cirrhosis compared with the control group. OPG levels were higher in patients with alcoholic liver cirrhosis than in the controls, whereas the levels of α-Klotho were comparable in the cirrhosis and control groups. No statistically significant differences in the concentrations of fetuin-A, OPG and α-Klotho protein were demonstrated according to type of liver cirrhosis. The findings of the present study revealed a significant negative correlation between the level of α-Klotho protein and C-reactive protein in the patients with alcoholic liver cirrhosis. Concentrations of fetuin-A were lower, whereas those of OPG were higher, in the alcoholic liver cirrhosis group compared with the control group. Fetuin-A, OPG and α-Klotho may not be good indicators of liver cirrhosis severity. In conclusion, fetuin-A and OPG may be used in the diagnosis of liver cirrhosis.

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“…In vitro studies showed that aKlotho induces autophagy in cancer cell lines. 44,82 The in vivo effects of aKlotho on autophagy in intact animals have not been described. We showed that autophagic activity is upregulated in Tg-Kl mice at baseline as evidenced by significant p62 reduction and mild increase in LC3-II formation compared with in WT mice.…”

Section: Discussionmentioning

confidence: 99%

“…[38][39][40] Associations between the levels of autophagy and aKlotho have previously been reported, but the results were not consistent. [41][42][43][44] Furthermore, whether the renoprotection rendered by aKlotho is related to modulation of autophagy has not been studied.…”

mentioning

confidence: 99%

αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy

Shi¹,

Flores²,

Gillings³

et al. 2015

JASN

147

209

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AKI confers increased risk of progression to CKD. aKlotho is a cytoprotective protein, the expression of which is reduced in AKI, but the relationship of aKlotho expression level to AKI progression to CKD has not been studied. We altered systemic aKlotho levels by genetic manipulation, phosphate loading, or aging and examined the effect on long-term outcome after AKI in two models: bilateral ischemia-reperfusion injury and unilateral nephrectomy plus contralateral ischemia-reperfusion injury. Despite apparent initial complete recovery of renal function, both types of AKI eventually progressed to CKD, with decreased creatinine clearance, hyperphosphatemia, and renal fibrosis. Compared with wild-type mice, heterozygous aKlotho-hypomorphic mice (aKlotho haploinsufficiency) progressed to CKD much faster, whereas aKlotho-overexpressing mice had better preserved renal function after AKI. High phosphate diet exacerbated aKlotho deficiency after AKI, dramatically increased renal fibrosis, and accelerated CKD progression. Recombinant aKlotho administration after AKI accelerated renal recovery and reduced renal fibrosis. Compared with wild-type conditions, aKlotho deficiency and overexpression are associated with lower and higher autophagic flux in the kidney, respectively. Upregulation of autophagy protected kidney cells in culture from oxidative stress and reduced collagen 1 accumulation. We propose that aKlotho upregulates autophagy, attenuates ischemic injury, mitigates renal fibrosis, and retards AKI progression to CKD.

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Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells

Abstract: Klotho is a tumor suppressor that, through the regulation of IGF-1R phosphorylation and subsequent activation of downstream Akt-p70S6K and ERK signaling, regulates HCC tumor cell proliferation, apoptosis, autophagy and invasion.

Cited by 59 publications

References 27 publications

Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis

αKlotho Mitigates Progression of AKI to CKD through Activation of Autophagy

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