Transcriptional upregulation of human cathepsin L by VEGF in glioblastoma cells

Keerthivasan, Shilpa; Keerthivasan, Ganesan; Mittal, S.R.; Chauhan, Shyam S.

doi:10.1016/j.gene.2007.05.002

Cited by 26 publications

(23 citation statements)

References 42 publications

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“…This effect appears to be mediated via c-Jun N-terminal kinase (JNK) pathway [144]. These data fit well with the findings highlighting a close relationship between Cathepsin L and MMP and/or uPA, in facilitating tumor angiogenesis [46,[143][144][145][146][147]. In this scenario, Keerthivasan et al [145] have recently shown that, at least in U87MG glioblastoma cells, vascular endothelial growth factor (VEGF) may up-regulate, at the transcriptional level, Cathepsin L. In line with these observations, Chang et al [148] have reported that, in human breast cancer cells, VEGF-A may promote angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, thus causing basement membrane degradation.…”

Section: Cathepsin L and Cancer-related Bone Diseasessupporting

confidence: 84%

Cathepsin L in Normal and Pathological Bone Remodeling

Leto

Crescimanno

Flandina

et al. 2011

Clinic Rev Bone Miner Metab

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Cathepsin L is a ubiquitous lysosomal cysteine endopeptidase that is mainly involved in the metabolic turnover of intracellular proteins. However, it is now well established that this enzyme may also be implicated in the regulation of other important biological processes including bone resorption. Therefore, altered expression levels of Cathepsin L may result in disturbances of bone homeostasis and, eventually, in the onset of pathological conditions associated with altered bone turnover. These observations support the concept that Cathepsin L may be regarded as an additional target for the development of novel therapeutic options for the treatment of patients with bone diseases. This review provides insight into the most recent advances in understanding the role of Cathepsin L in normal and pathological bone remodeling and discusses the potential clinical and therapeutic applications related to these findings.

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Section: Cathepsin L and Cancer-related Bone Diseasessupporting

confidence: 84%

Cathepsin L in Normal and Pathological Bone Remodeling

Leto

Crescimanno

Flandina

et al. 2011

Clinic Rev Bone Miner Metab

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“…Further, key proangiogenic factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) have been shown to induce CTSL expression. Keerthivasan et al identified a 47 base pair VEGF responsive element in CTSL promoter region and demonstrated that VEGF stimulation induces CTSL transcription in glioblastoma cells [41]. A strong positive correlation between VEGF and CTSL expression status has been reported in adult chronic myeloid leukemia and pediatric acute myeloid leukemia patients [42, 43].…”

Section: Discussionmentioning

confidence: 99%

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

Sudhan

Rabaglino

Wood

et al. 2016

Clin Exp Metastasis

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A significant proportion of breast cancer patients harbor clinically undetectable micrometastases at the time of diagnosis. If left untreated, these micrometastases may lead to disease relapse and possibly death. Hence, there is significant interest in the development of novel anti-metastatic agents that could also curb the growth of pre-established micrometastases. Like primary tumor, the growth of metastases also is driven by angiogenesis. Although the role of cysteine protease Cathepsin L (CTSL) in metastasis associated tumor cell functions such as migration and invasion is well recognized, its role in tumor angiogenesis remains less explored. The present study examines the contribution of CTSL to breast cancer angiogenesis and evaluates the anti-angiogenic efficacy of CTSL inhibitor KGP94. CTSL semi-quantitative RT-PCR analysis on breast tissue panels revealed significant upregulation of CTSL in breast cancer patients which strongly correlated with increased relapse and metastatic incidence and poor overall survival. Preclinically, CTSL ablation using shRNA or KGP94 treatment led to a significant reduction in MDA-MB-231 tumor cell induced angiogenesis in vivo. In-vitro assessments demonstrated a significant decrease in various angiogenic properties such as endothelial cell sprouting, migration, invasion, tube formation and proliferation in the presence of KGP94. Microarray analyses revealed a significant upregulation of cell cycle related genes by CTSL. Western blot analyses further confirmed upregulation of members of the cyclin family by CTSL. Collectively, these data indicate that CTSL is an important contributor to tumor angiogenesis and that the CTSL inhibition may have therapeutic utility in the treatment of breast cancer patients.

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“…This protein has been hypothesized to be a significant driver of apoptosis resistance in GBM through the inhibition of caspase-3 and -7 activation and p53 function as described earlier. The substantial resistance to apoptosis caused by Bcl2L12 and elevation of other necrotic cell death mediators such as cathepsins, have been proposed to be causal factors for the widespread necrosis found in these tumors [49-51]. The idea of programmed necrosis has been hypothesized and debated for many years, but recently came to the forefront with the seminal study by Degterev et al in which they coined the term “necroptosis” to describe a specific form of non-apoptotic programmed necrotic cell death [52].…”

Section: Necrosis/necroptosismentioning

confidence: 99%

How to train glioma cells to die: molecular challenges in cell death

2015

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The five-year survival rate for patients with malignant glioma is less than 10%. Despite aggressive chemo/radiotherapy these tumors have remained resistant to almost every interventional strategy evaluated in patients. Resistance to these agents is attributed to extrinsic mechanisms such as the tumor microenvironment, poor drug penetration, and tumoral heterogeneity. In addition, genetic and molecular examination of these tumors has revealed defective apoptotic regulation, enhanced pro-survival autophagy signaling, and a propensity for necrosis that aids in the adaptation to environmental stress and resistance to treatment. The combination of extrinsic and intrinsic hallmarks in glioma contributes to the multifaceted resistance to traditional anti-tumor agents. Here we describe the biology of the disease relevant to therapeutic resistance, with a specific focus on molecular deregulation of cell death pathways. Emerging studies investigating the targeting of these pathways including BH3 mimetics and autophagy inhibitors are being evaluated in both the preclinical and clinical settings are discussed. This review highlights the pathways exploited by glioblastoma cells that drive their hallmark pro-survival predisposition and makes therapy development such a challenge. Keywords glioma; apoptosis; autophagy; necrosis; resistance While primary malignant brain tumors are rare, the 5-year survival for these patients is dismal at approximately 10%. Utilizing the World Health Organization based classification, these tumors are categorized as low-grade (I-II) or high-grade malignant gliomas (III-IV) [1]. Specifically, grade IV glioma or glioblastoma (GBM) [2] are the most common and destructive form of malignant glioma. Headaches, seizures, cognitive and personality changes, gait imbalance, sensory loss, and incontinence are common symptoms and can be dependent on the location of the tumor. Symptomatic management for these patients consists mainly of steroids to relieve neurological symptoms associated with edema and Despite aggressive surgical resection and concurrent chemo/radiotherapy 70% of patients diagnosed with GBM will succumb to the disease within two years. A better understanding of the molecular changes in these malignant cells in response to therapy is necessary to unveil how these malignant cells can survive intense chemo/radiation insult. Recent studies have identified numerous mechanisms by which cells "commit suicide" (Fig. 1) and a better understanding of the mechanisms of cell death exploited by different therapeutics is essential for the rational design of future therapeutic strategies. Here we discuss the current treatment strategies utilized to kill GBM cells, and various cell death mechanisms relevant to glioma destruction and resistance. HHS Public Access ApoptosisApoptosis is perhaps the most well studied form of cellular demise consisting of an energydependent cascade of molecular signaling typically involving the cysteine-dependent aspartate-directed proteases called caspases. Caspase-dep...

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Transcriptional upregulation of human cathepsin L by VEGF in glioblastoma cells

Cited by 26 publications

References 42 publications

Cathepsin L in Normal and Pathological Bone Remodeling

Cathepsin L in Normal and Pathological Bone Remodeling

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

How to train glioma cells to die: molecular challenges in cell death

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