Upregulation of the cysteine protease inhibitor, cystatin SN, contributes to cell proliferation and cathepsin inhibition in gastric cancer

Choi, Eun Hwa; Kim, Jong-Tae; Kim, Joo Heon; Kim, Soo Young; Song, Eun Young; Kim, Jae Wha; Kim, Seon‐Young; Yeom, Young Il; Kim, Ik Hwan; Lee, Hee Gu

doi:10.1016/j.cca.2009.05.008

Cited by 59 publications

(77 citation statements)

References 30 publications

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“…33, 34, 35 Paradoxically, CST1 has been proposed to be a novel marker in several tumors, including non-small cell lung cancer, pancreatic cancer, colorectal cancer and gastric cancer. 8, 9, 10, 11 The upregulated expression of CST1 is associated with proliferation, invasion and metastasis of cells, which are the main characteristics of tumor malignancy. 8, 10, 36 To date, the cooperative effect of CatB and CST1 during tumorigenesis remains poorly defined.…”

Section: Discussionmentioning

confidence: 99%

“…8, 9, 10, 11 The upregulated expression of CST1 is associated with proliferation, invasion and metastasis of cells, which are the main characteristics of tumor malignancy. 8, 10, 36 To date, the cooperative effect of CatB and CST1 during tumorigenesis remains poorly defined. In this study, we observed that extracellular CatB activity was positively regulated by CST1 expression and negatively regulated GS activity, inducing abnormal glycogen accumulation, which is a direct cause of cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

“…7 Cystatin SN (CST1), encoded by CST1, is a member of the type 2 cystatin family, and the induction of CST1 expression is associated with tumorigenesis, increased cancer cell proliferation and invasion, and tumor recurrence. 8, 9, 10, 11 As CatB is a functional protease and CST1 is its inhibitor, it is highly paradoxical that both of them contribute to tumorigenesis. To date, the underlying relationship between CST1 and CatB, and their roles in tumor development, remains poorly understood.…”

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confidence: 99%

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Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation

Park

Lee

et al. 2017

Cell Death Dis

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Cystatin SN (CST1), a known inhibitor of cathepsin B (CatB), has important roles in tumor development. Paradoxically, CatB is a member of the cysteine cathepsin family that acts in cellular processes, such as tumor development and invasion. However, the relationship between CST1 and CatB, and their roles in tumor development are poorly understood. In this study, we observed that the knockdown of CST1 induced the activity of senescence-associated β-galactosidase, a marker of cellular senescence, and expression of senescence-associated secretory phenotype genes, including interleukin-6 and chemokine (C-C motif) ligand 20, in MDA-MB-231 and SW480 cancer cells. Furthermore, CST1 knockdown decreased extracellular CatB activity, and direct CatB inhibition, using specific inhibitors or shCatB, induced cellular senescence. Reconstitution of CST1 restored CatB activity and inhibited cellular senescence in CST1 knockdown cells. CST1 knockdown or CatB inhibition increased glycogen synthase (GS) kinase 3β phosphorylation at serine 9, resulting in the activation of GS and the induction of glycogen accumulation associated with cellular senescence. Importantly, CST1 knockdown suppressed cancer cell proliferation, soft agar colony growth and tumor growth in a xenograft model. These results indicate that CST1-mediated extracellular CatB activity enhances tumor development by preventing cellular senescence. Our findings suggest that antagonists of CST1 or inhibitors of CatB are potential anticancer agents.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation

Park

Lee

et al. 2017

Cell Death Dis

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“…Cystatin SN (salivary, neutral) is found to be upregulated in gastric cancers compared to noncancerous tissues and correlated with a tumor staging system (Choi et al, 2009). Downregulation of cystatin SN with siRNA both decreases cell proliferation and increases cathepsin activity in gastric cancer cells.…”

Section: Type II Cystatinsmentioning

confidence: 99%

Cystatins as regulators of cancer

Cox¹

2017

MRAJ

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“…Decreased levels of cystatin C were found in the plasma of mice with Lewis lung adenocarcinoma (12), and cystatin E/M is a suppressor gene of cervical and breast cancer (13,14). One member of the salivary cystatins (cystatin SN) also was found to be differentially regulated (acti-vated or suppressed) in cancerous lesions of gastric cancer patient tissues (15).…”

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confidence: 99%

Identification of Cystatin SA as a Novel Inhibitor of Acid Ceramidase

Eliyahu

Shtraizent

et al. 2011

Journal of Biological Chemistry

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Background: Acid ceramidase is an enzyme of sphingolipid metabolism whose cellular activity is carefully regulated. Results: Cystatin SA inhibits acid ceramidase activity without affecting precursor processing. Small peptides derived from cystatin SA also are inhibitory. Conclusion: Cystatin SA inhibits acid ceramidase activity and contributes to the regulation of this enzyme function. Significance: The first physiological inhibitor of acid ceramidase has been described.

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Upregulation of the cysteine protease inhibitor, cystatin SN, contributes to cell proliferation and cathepsin inhibition in gastric cancer

Cited by 59 publications

References 30 publications

Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation

Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation

Cystatins as regulators of cancer

Identification of Cystatin SA as a Novel Inhibitor of Acid Ceramidase

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