Decreased Level of Klotho Contributes to Drug Resistance in Lung Cancer Cells: Involving in Klotho-Mediated Cell Autophagy

Chen, Tianjun; Ren, Hui; Thakur, Asmitananda; Tian, Yang; Yang, Li V.; Zhang, Shuo; Wang, Ting; Chen, MingWei

doi:10.1089/dna.2016.3437

Cited by 18 publications

(16 citation statements)

References 32 publications

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“…The association between Klotho and autophagy has been reported in various diseases, such as Alzheimer's disease, acute kidney injury, chronic obstructive pulmonary disease, and lung cancer (12)(13)(14)(15). These findings suggest that Klotho has an important role in the pathogenesis of those diseases.…”

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confidence: 78%

Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

et al. 2018

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Recently, we showed that tacrolimus‐induced renal injury was closely associated with impairment of autophagy clearance, and Klotho deficiency aggravated tacrolimus‐induced renal injury. In this study, we evaluated the effect of Klotho treatment on autophagy clearance in tacrolimus‐induced renal injury. We evaluated the effect of Klotho on tacrolimus‐induced renal injury in an experimental mouse model and in vitro by treatment with tacrolimus and/or recombinant mouse Klotho. In vivo and in vitro studies showed that tacrolimus treatment impaired lysosomal acidification and decreased cathepsin B activity, expression of lysosome‐associated membrane protein 2, and expression of transcription factor EB (TFEB), a master regulator for lysosomal biogenesis. These results were improved by Klotho treatment. Moreover, addition of bafilomycin A1, an inhibitor of lysosomal function, abolished the protective effect of Klotho, indicating that the protective effect of Klotho was closely associated with lysosome function. Klotho induced nuclear translocation of TFEB through inhibition of phosphorylation of glycogen synthase kinase 3β (GSK3β) by confirming using CHIR99021, a GSK3β inhibitor. Collectively, our data suggest that Klotho improves autophagy clearance via activation of lysosomal function in tacrolimus‐induced nephrotoxicity.—Lim, S. W., Shin, Y. J., Luo, K., Quan, Y., Ko, E. J., Chung, B. H., Yang, C. W. Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury. FASEB J. 33, 2694–2706 (2019). http://www.fasebj.org

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confidence: 78%

Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

et al. 2018

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“…The tumor suppressive function of Klotho has been reported in several human solid malignancies, but less in hematological cancers, especially in lymphoma (16)(17)(18)(19). Lower Klotho expression was detected in T-cell lymphoma tissues whereas high expression level of Klotho was observed in normal lymph (17,20,21). Additionally, Klotho decline has a significant prognostic value in cancers, such as large cell neuroendocrine carcinoma (LCNEC), small cell lung cancer (SCLC) and hepatocellular carcinoma (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Klotho suppresses tumor progression via inhibiting IGF-1R signaling in T-cell lymphoma

et al. 2017

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Klotho is a transmembrane protein and acts as an upstream modulator of insulin-like growth factor-1 receptor (IGF-1R) signaling, which was indicated to be involved in the pathogenesis of solid cancer and hematological malignancies, including T‑cell lymphoma. Although Klotho was recently identified as a tumor suppressor in several types of human malignancies, the potential role of Klotho in T‑cell lymphoma has not been reported. In the present study, we investigated the expression level and the molecular events of Klotho in T‑cell lymphoma. Significantly lower expression of Klotho was observed in T‑cell lymphoma patient samples compared to normal lymph nodes. Functional analysis after Klotho overexpression revealed significantly inhibited tumor cell viability in T‑cell lymphoma. Moreover, apoptosis of T‑cell lymphoma cells were induced after transfected with Klotho-overexpressing vectors. Forced expression of Klotho resulted in decline of activation of IGF-1R signaling, accompanied by decreased phosphorylation of its downstream targets, including AKT and ERK1/2. These data indicated that Klotho acts as a tumor suppressor via inhibiting IGF-1R signaling, thus suppressing the viability and promoting apoptosis in T‑cell lymphoma. Taken together, Klotho may serve as a potential target for the therapeutic intervention of T‑cell lymphoma.

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“…docetaxel resistance is a critical issue in treating advanced nSclc, and its potential underlying mechanisms have been elucidated, including the implication of intracellular multidrug resistance-associated protein P-glycoprotein, lung resistance protein, glutathione transferase and t-structural changes of intracellular microtubules topoisomerase (26). In addition, it has been reported that high-mobility group box 1-mediated autophagy contributes to docetaxel resistance in lung adenocarcinoma (27), while another study revealed that Klotho-mediated autophagy was closely involved in chemotherapy resistance (including docetaxel resistance) in lung cancer (28). in the present study, it was also demonstrated that autophagy attenuated the cytotoxic effects of docetaxel on a549/dTX cells, which was in line with these previous findings.…”

Section: Docetaxel Group Apatinib Plus Docetaxel Group --------------mentioning

confidence: 99%

Apatinib sensitizes chemoresistant NSCLC cells to doxetaxel via regulating autophagy and enhances the therapeutic efficacy in advanced and refractory/recurrent NSCLC

Hui

et al. 2020

Mol Med Rep

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The prognosis of advanced non-small cell lung cancer (nSclc) is poor; therefore, identifying novel treatment strategies for patients with nSclc is important. The present study aimed to investigate the efficacy of apatinib plus docetaxel vs. docetaxel alone, as well as their effects on regulating autophagy markers in patients with advanced nSclc. Furthermore, it was evaluated whether apatinib sensitized chemoresistant nSclc cells to docetaxel via regulating autophagy. a total of 39 patients with advanced nSclc were consecutively enrolled and treated with apatinib plus docetaxel (n=19) or docetaxel alone (n=20) for four treatment cycles. The treatment response, adverse events and expression levels of autophagy markers [(light chain 3 α (lc3a) and Beclin-1] were evaluated in tumor samples, which were obtained via biopsy, before treatment and after 2-cycle treatment. In addition, in a mechanistic in vitro experiment, apatinib, docetaxel, the autophagy activator rapamycin and the autophagy inhibitor 3-methyladenine (3-Ma) were used to treat docetaxel-resistant A549 (A549/DTX) cells alone or in various combinations. The expression levels of LC3A, Beclin-1, poly (ADP) ribose polymerase (ParP) and phosphorylated (p)-aKT were detected via western blotting, while the cell apoptosis rate was detected with an annexin V/Pi assay. The overall remission rate (37 vs. 10%; P=0.047) and disease control rate (84 vs. 45%; P=0.011) were increased in the Apatinib plus docetaxel group compared with the docetaxel group. Most of the adverse events were mild and tolerable, and there was no difference between the two groups except for total hypertension and hand-foot syndrome, which were higher in the Apatinib plus docetaxel group). compared with the levels prior to treatment, Beclin-1 and lc3a remained unchanged post-treatment in the Apatinib plus docetaxel group, while they were increased in the docetaxel group. docetaxel increased lc3a, Beclin-1 and p-aKT expression levels, ParP cleavage and the cell apoptosis rate in a549/dTX cells, and rapamycin further enhanced, while 3-Ma reduced these effects of docetaxel. Moreover, apatinib repressed LC3A, Beclin-1, p-AKT expression levels and promoted the cell apoptosis rate in a549/dTX cells and docetaxel-treated a549/dTX cells. in conclusion, apatinib synergize the effect of docetaxel in treating patients with advanced nSclc and chemoresistant nSclc cells via inhibiting autophagy.

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Decreased Level of Klotho Contributes to Drug Resistance in Lung Cancer Cells: Involving in Klotho-Mediated Cell Autophagy

Cited by 18 publications

References 32 publications

Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

Effect of Klotho on autophagy clearance in tacrolimus‐induced renal injury

Klotho suppresses tumor progression via inhibiting IGF-1R signaling in T-cell lymphoma

Apatinib sensitizes chemoresistant NSCLC cells to doxetaxel via regulating autophagy and enhances the therapeutic efficacy in advanced and refractory/recurrent NSCLC

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