Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer

Xie, Biao; Zhou, Jianping; Shu, Guoshun; Liu, Dongcai; Jiapeng, Zhou; Chen, Jinhui; Yuan, Long

doi:10.1186/1475-2867-13-18

Cited by 79 publications

(67 citation statements)

References 25 publications

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“…The anti-proliferation effect of sesquiterpenoids on human breast adenocarcinoma MCF-7, human intestinal adenocarcinoma HCT-8, human lung carcinoma A-549, human gastric cancer SGC-7901 and human hepatocarcinoma BEL-7402 cells were studied using a CCK-8 assay, which has commonly been used to investigate the cytotoxicity of compounds (15). The results are presented in Table I.…”

Section: Sesquiterpenoids Isolated From S Lyratummentioning

confidence: 99%

Anticancer activity of sesquiterpenoids extracted from Solanum lyratum via the induction of mitochondria-mediated apoptosis

Chen¹,

Wu²,

Zhang³

et al. 2016

Oncology Letters

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Abstract. Sesquiterpenoids are a major type of compound found in Solanum lyratum (S. lyratum). The present study aimed to investigate whether sesquiterpenoids from S. lyratum demonstrated cytotoxicity against the MCF-7, HCT-8, A-549, SGC-7901 and BEL-7402 cell lines, and the mechanism of solajiangxin H and lyratol D, which exhibited high cytotoxicity against SGC-7901 cells (half maximal inhibitory concentration, IC 50 =4.8 and 5.9 µg/ml), was associated with mitochondria-mediated apoptosis. The results of the Cell Counting Kit-8 assay indicated that 15 sesquiterpenoids had cytotoxicity against the aforementioned cultured cells. The results of DAPI staining and western blot analysis, used to study the anticancer mechanisms of solajiangxin H and lyratol D in SGC-7901 cells, suggested that solajiangxin H and lyratol D induced the apoptosis of SGC-7901 cells significantly (P<0.01), downregulated the expression of the antiapoptotic proteins B-cell lymphoma (Bcl)-2 and survivin, and upregulated the expression of the proapoptotic proteins Bcl-2-like protein 4, second mitochondria-derived activator of caspase, cleaved (c)-caspase-3 and c-caspase-9. The present study therefore demonstrated that 15 sesquiterpenoids from S. lyratum exhibited anticancer activity in MCF-7, HCT-8, A-549, SGC-7901 and BEL-7402 cells, and that the anticancer mechanisms of solajiangxin H and lyratol D may be associated with mitochondria-mediated apoptosis. Additionally, the present study provides evidence in support of the hypothesis that S. lyratum may be a promising candidate for the development of novel cancer therapies.

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Section: Sesquiterpenoids Isolated From S Lyratummentioning

confidence: 99%

Anticancer activity of sesquiterpenoids extracted from Solanum lyratum via the induction of mitochondria-mediated apoptosis

Chen¹,

Wu²,

Zhang³

et al. 2016

Oncology Letters

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“…Regarding KLOTHO as a tumor suppressor, in cultured gastric cancer cells KLOTHO downregulates type 1 IGF receptor (IGF1R) phosphorylation and the ensuing activation of IRS-1/PI3K/AKT/mTOR signaling, thereby modulating cell proliferation, apoptosis, and autophagy (439). In human embryonic kidney cells, the KLOTHO-FGF19 complex attenuated the activation of AKT and mTOR accompanied by ERK1/2 activation, which is thought to underlie pro-apoptotic actions (266).…”

Section: (See the Role Of Sirtuins In Cr)mentioning

confidence: 99%

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Cavanagh

Inserra

Ferder

2015

American Journal of Physiology-Heart and Circulatory Physiology

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de Cavanagh EM, Inserra F, Ferder L. Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol 309: H15-H44, 2015. First published May 1, 2015; doi:10.1152/ajpheart.00459.2014, renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca 2ϩ , phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease. mechanistic target of rapamycin; vitamin D; caloric restriction; renin-angiotensin system EFFORTS AIMED AT DECIPHERING the mechanisms that underlie the aging process have unveiled three interventions that can increase survival and retard age-related diseases from lower organisms to mammals, i.e., caloric restriction (CR) (84,85,140,160,334), mechanistic target of rapamycin (mTOR; originally mammalian TOR) inhibition by rapamycin (173,196,281), and renin-angiotensin system blockade (RAS-bl) (20, 21, 26,63,253,284,354), although the latter has been less studied. In light of these findings, some intriguing questions come to mind: Do these interventions attenuate aging by interfering with common mechanisms? Do the mechanisms that are interfered with by CR, rapamycin, and RAS-bl mutually affect each other? Are there any pathways involved exclusively with a certain intervention?Previously (101), we have discussed the converging effects d...

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“…In the past years klotho has emerged as a potent tumor suppressor in a wide array of malignancies, including breast, pancreas, colon, gastric, and lung cancers, as well as in melanoma (9,10,(13)(14)(15)(16). We have previously shown that klotho is abundantly expressed in normal breast and pancreatic tissues and that upon malignant transformation its expression is reduced (9,10,17).…”

Section: Introductionmentioning

confidence: 99%

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Ligumsky

Rubinek

Merenbakh-Lamin

et al. 2015

Molecular Cancer Research

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Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Overexpression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities.Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer.

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Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer

Cited by 79 publications

References 25 publications

Anticancer activity of sesquiterpenoids extracted from Solanum lyratum via the induction of mitochondria-mediated apoptosis

Anticancer activity of sesquiterpenoids extracted from Solanum lyratum via the induction of mitochondria-mediated apoptosis

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

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