Cathepsin B is a target of Hedgehog signaling in pancreatic cancer

Hwang, Jung‐Won; Lee, Sang Hyub; Lee, Kwang Hyuck; Lee, Keung Youp; Kim, Haeryoung; Ryu, Ji Kon; Yoon, Yong Bum; Kim, Yong‐Tae

doi:10.1016/j.canlet.2008.08.028

Cited by 28 publications

(18 citation statements)

References 30 publications

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“…Kinases and phosphatases have long been understood to interact in regulatory networks such as those proposed for proteases and their endogenous inhibitors. Interestingly, CTSB has been found to be involved in activation of signaling cascades of MAPK and PI3 kinase in the context of tumor cell proliferation and metastasis (11,36). Our findings revealed that the phosphorylation of p38, JNK, ERK, and Akt in the HBSP-3 cells was increased in the HBSP-expressing cells and can be abolished by the introduction of siRNA against HBSP or CTSB.…”

Section: Discussionmentioning

confidence: 62%

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Chen

Jiao

et al. 2012

J Virol

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C hronic hepatitis B virus (HBV) infection has been proven to be one of the most important risk factors for the development of hepatocellular carcinoma (HCC) (3, 9). However, the pathogenesis of cancer in HBV infection is still not fully understood, and it appears that multiple factors and cellular signaling pathways are involved in hepatocarcinogenesis (28). Integration of HBV genome into host DNA can lead to alterations in cellular gene function or generate chromosomal instability (1, 10, 43). Expression of some oncogenic HBV proteins such as HBx and truncated Pre-S2/S has been shown to have a direct effect on malignant transformation of the liver (42) and to promote metastasis of the malignant cells, and there is thus a very high mortality rate for HCC patients (18). Another HBV protein, encoded by a singly spliced 2.2-kb HBV DNA and referred to as the hepatitis B spliced protein (HBSP), is found to be expressed in liver biopsy tissues from four out of five chronic patients but not from two hepatitis C virus-infected patient samples and one normal liver sample (39). Our prior study also showed that a 2.2-kb splice variant was present in all tumor and peritumor samples from 12 HCC patients studied (20). Exogenous expression of HBSP in transfected Huh-7 cells can induce cell apoptosis (40). However, the cytopathic effect of the HBSP was unclear, and its role in progression, invasion, and metastasis of HBV-related HCC has not yet been elucidated.We previously showed that cathepsin B (CTSB) was one of the major intracellular interacting partners of HBSP, and it was identified using a yeast two-hybrid screening assay (8). This led us to investigate whether the HBSP could interact with CTSB in the context of hepatoma cells to affect cell migration, invasion, and metastasis, all of which can be modulated by CTSB acting directly and indirectly on extracellular matrix (ECM) component remodeling and degradation (26,47). CTSB is a lysosomal cysteine protease that plays an important role in physiological protein turnover and processing (19,41). In nonmalignant cells, CTSB is mainly stored in the lysosome, whereas in malignant cells, CTSB redistributes into exocytic vesicles at the cell periphery, leading to its secretion and association with binding partners on the tumor cell surface (22,33). CTSB can cleave and activate a wide variety of substrates in proteolytic pathways that increase neoplastic progression. It has been shown that activation of urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) by CTSB not only enhances ECM degradation and cancer cell motility and invasion (14) but also induces in vitro angiogenesis (2). In addition to interacting with other proteases, CTSB may regulate the activity of kinase signaling networks, cell surface receptors, and signaling molecules such as chemokines, cytokines and growth factors (25). However, such interactions are usually bidirectional because kinases can also regulate many proteases through phosphorylation while proteases can control the actio...

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Section: Discussionmentioning

confidence: 62%

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Chen

Jiao

et al. 2012

J Virol

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“…Hedgehog (Hh) signaling is involved in pancreatic cancer development and can regulate invasion by increasing cathepsin B expression. Hwang et al [95] treated the PANC-1 cell line with cyclopamine (Hh signal inhibitor) and found a dose-dependent decrease in cathepsin B expression at both the mRNA and protein levels and reduced cell invasiveness [95]. However, under other conditions, cathepsin B might mediate cancer cell apoptosis.…”

Section: Pancreatic Cancermentioning

confidence: 99%

Cathepsins in digestive cancers

et al. 2017

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Cathepsins are lysosomal peptidases belonging to the papain family, and based on their catalytic sites, these enzymes can be divided into serine, cysteine and aspartic proteases. The studies conducted to date have identified, 15 types of cathepsins that are widely distributed in intracellular and extracellular spaces. These proteases participate in various pathological activities, including the occurrence and development of human cancers. Several recent studies suggest that cathepsins, particularly cathepsins B, D, E and L, contribute to digestive tumorigenesis. Cathepsins were found to promote the development of most digestive cancers except liver cancer, in which they might have the opposite effects. Due to their important roles in digestive tumors, cathepsins might be therapeutic targets for the treatment of digestive cancers.

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“…It has recently been suggested that SHH signaling progresses during colon carcinogenesis [25], [26] and in metastatic disease [27] whereas in normal colonic tissue, SHH signaling is involved in differentiation [28]. Recently, genes have been profiled that are regulated downstream of Gli1 and Gli2 that are involved in cell proliferation and cell cycle [29], [30], and cell survival (PDGFRα and Bcl-2) [22]. Gli2 is also expressed in many basal cell carcinomas [31], suggesting that these genes might also be involved in the development of PC, which could be consistent with its partial action as mediator of SHH signals [32].…”

Section: Introductionmentioning

confidence: 99%

Hedgehog Signaling Antagonist GDC-0449 (Vismodegib) Inhibits Pancreatic Cancer Stem Cell Characteristics: Molecular Mechanisms

et al. 2011

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BackgroundRecent evidence from in vitro and in vivo studies has demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSCs). Therefore, the chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. GDC-0449 (Vismodegib), orally administrable molecule belonging to the 2-arylpyridine class, inhibits SHH signaling pathway by blocking the activities of Smoothened. The objectives of this study were to examine the molecular mechanisms by which GDC-0449 regulates human pancreatic CSC characteristics in vitro.Methodology/Principal FindingsGDC-0499 inhibited cell viability and induced apoptosis in three pancreatic cancer cell lines and pancreatic CSCs. This inhibitor also suppressed cell viability, Gli-DNA binding and transcriptional activities, and induced apoptosis through caspase-3 activation and PARP cleavage in pancreatic CSCs. GDC-0449-induced apoptosis in CSCs showed increased Fas expression and decreased expression of PDGFRα. Furthermore, Bcl-2 was down-regulated whereas TRAIL-R1/DR4 and TRAIL-R2/DR5 expression was increased following the treatment of CSCs with GDC-0449. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GDC-0449-treated pancreatic CSCs. Thus, activated Gli genes repress DRs and Fas expressions, up-regulate the expressions of Bcl-2 and PDGFRα and facilitate cell survival.Conclusions/SignificanceThese data suggest that GDC-0499 can be used for the management of pancreatic cancer by targeting pancreatic CSCs.

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Cathepsin B is a target of Hedgehog signaling in pancreatic cancer

Cited by 28 publications

References 30 publications

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Interaction of the Hepatitis B Spliced Protein with Cathepsin B Promotes Hepatoma Cell Migration and Invasion

Cathepsins in digestive cancers

Hedgehog Signaling Antagonist GDC-0449 (Vismodegib) Inhibits Pancreatic Cancer Stem Cell Characteristics: Molecular Mechanisms

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