Lysosomal Degradation of CD44 Mediates Ceramide Nanoliposome-induced Anoikis and Diminished Extravasation in Metastatic Carcinoma Cells

Haakenson, Jeremy K.; Khokhlatchev, Andrei; Choi, Youngshim; Linton, Samuel S.; Zhang, Pu; Zaki, Peter; Fu, Chen; Cooper, Timothy K.; Manni, Andrea; Zhu, Junjia; Fox, Todd E.; Dong, Chuan; Kester, Mark

doi:10.1074/jbc.m114.609677

Cited by 16 publications

(10 citation statements)

References 38 publications

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“…Different strategies aiming the impairment of CD44-dependent cancer cell migration have been proposed. The ceramide nanoliposome (CNL) was shown to induce anoikis and to limit metastasis by inducing lysosomal degradation of CD44 in PDAC cells ( 121 ).…”

Section: Glycosylation Alteration In Gastrointestinal Cancersmentioning

confidence: 99%

Glycomic Approaches for the Discovery of Targets in Gastrointestinal Cancer

et al. 2016

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Gastrointestinal (GI) cancer is the most common group of malignancies and many of its types are among the most deadly. Various glycoconjugates have been used in clinical practice as serum biomarker for several GI tumors, however, with limited diagnose application. Despite the good accessibility by endoscopy of many GI organs, the lack of reliable serum biomarkers often leads to late diagnosis of malignancy and consequently low 5-year survival rates. Recent advances in analytical techniques have provided novel glycoproteomic and glycomic data and generated functional information and putative biomarker targets in oncology. Glycosylation alterations have been demonstrated in a series of glycoconjugates (glycoproteins, proteoglycans, and glycosphingolipids) that are involved in cancer cell adhesion, signaling, invasion, and metastasis formation. In this review, we present an overview on the major glycosylation alterations in GI cancer and the current serological biomarkers used in the clinical oncology setting. We further describe recent glycomic studies in GI cancer, namely gastric, colorectal, and pancreatic cancer. Moreover, we discuss the role of glycosylation as a modulator of the function of several key players in cancer cell biology. Finally, we address several state-of-the-art techniques currently applied in this field, such as glycomic and glycoproteomic analyses, the application of glycoengineered cell line models, microarray and proximity ligation assay, and imaging mass spectrometry, and provide an outlook to future perspectives and clinical applications.

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Section: Glycosylation Alteration In Gastrointestinal Cancersmentioning

confidence: 99%

Glycomic Approaches for the Discovery of Targets in Gastrointestinal Cancer

et al. 2016

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“… 5 , 6 Our laboratory has developed a nanoliposomal formulation of C6-ceramide (CNL), which is an effective anti-tumorigenic agent in vivo in several cancer models. 7–13 Specifically in CLL, we have demonstrated that CNL selectively targets the Warburg effect by causing downregulation of glyceraldehyde 3-phosphate dehydrogenase and limits tumor growth in an in vivo murine model of CLL. 13 Additionally, inhibiting accumulation of intracellular ceramide prevents fludarabine-induced apoptosis in CLL cells.…”

Section: Introductionmentioning

confidence: 99%

STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia

Doshi

Shaw

Fox

et al. 2017

Sig Transduct Target Ther

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The pathogenesis of chronic lymphocytic leukemia (CLL) is poorly understood and it remains incurable with current therapies. We have previously shown that nanoliposomal C6-ceramide (CNL) is an effective therapy in an in vivo murine model of CLL. However, the key signaling pathways mediating CNL-induced cell death in CLL remains unknown. We hypothesized that CNL targets STAT3, a critical regulator of hematopoietic biology. We observed that CNL treatment reduced phosphorylated STAT3 at both Y705 and S727 residues in CLL cell lines and patient cells. This, in turn, reduced STAT3 transcriptional activity and expression of critical STAT3-dependent survival factors like Mcl-1 and survivin. The effect of CNL on STAT3 was further confirmed ex vivo as shown by reduced STAT3 phosphorylation in xenograft tumors obtained from mice treated with CNL. CNL suppressed STAT3 phosphorylation at Y705 and S727 through reduction in BTK activity and MEK1/2 kinase/PKC activities, respectively. Moreover, a synergistic reduction in CLL cell viability was observed on co-treatment with CNL and the BTK inhibitor, ibrutinib. Expression of an oncogenic form of STAT3 conferred partial resistance to CNL, providing confirmation that STAT3 mediates CNL-induced cell death. Taken together, these findings provide the first body of evidence demonstrating ceramide regulation of STAT3 phosphorylation. These results are also the first to demonstrate an effect of ceramide on BTK, a critical kinase mediating the B-cell receptor signaling in CLL cells and suggest a novel and synergistic combination of CNL and BTK inhibitors for CLL treatment.

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“…It has been reported that CD44 protein degradation in human breast and pancreatic cancer cells can occur through the lysosomal/autophagic pathway (43). In addition, CD44 degradation in head and neck squamous cell carcinoma cells was blocked by autophagy inhibitor CQ not by pretreatment with the proteasome inhibitor MG132 (27).…”

Section: Discussionmentioning

confidence: 92%

Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway

et al. 2020

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Hepatocellular carcinoma (HCC) is the most commonly diagnosed primary liver malignancy. The limited success with relapse of the disease in HCC therapy is frequently associated with the acquired resistance to anticancer drugs. To develop a strategy and design for overcoming the resistance of HCC cells to TNF-related apoptosis inducing ligand (TRAIL)-induced cell death, we evaluated the efficacy of a non-steroidal anti-inflammatory drug (NSAID) in combination with TRAIL against TRAIL-resistant HCC cells expressing a high level of CD44. We revealed by MTT and western blotting, respectively, that celecoxib (CCB), an NSAID, and 2,5-dimethyl celecoxib (DMC), a non-cyclooxygenase (COX)-2 inhibitor analog of CCB, were able to sensitize TRAIL-resistant HCC cells to TRAIL, implicating a COX-independent mechanism. CCB dose-dependently enhanced LC3-II and reduced p62 levels through AMPK activation and inhibition of the Akt/mTOR pathway and upregulated expression of ATF4/CHOP, leading to activation of endoplasmic reticulum (ER) stress-dependent autophagy. The TRAIL sensitization capacity of CCB in TRAIL-resistant HCC cells was abrogated by an ER stress inhibitor. In addition, we also revealed by flow cytometry and western blotting, respectively, that accelerated downregulation of TRAIL-mediated c-FLIP expression, DR5 activation and CD44 degradation/downregulation by NSAID resulted in activation of caspases and poly(ADP-ribose) polymerase (PARP), leading to the sensitization of TRAIL-resistant HCC cells to TRAIL and thereby reversal of TRAIL resistance. From these results, we propose that NSAID in combination with TRAIL may improve the antitumor activity of TRAIL in TRAIL-resistant HCC, and this approach may serve as a novel strategy that maximizes the therapeutic efficacy of TRAIL for clinical application.

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Lysosomal Degradation of CD44 Mediates Ceramide Nanoliposome-induced Anoikis and Diminished Extravasation in Metastatic Carcinoma Cells

Cited by 16 publications

References 38 publications

Glycomic Approaches for the Discovery of Targets in Gastrointestinal Cancer

Glycomic Approaches for the Discovery of Targets in Gastrointestinal Cancer

STAT3 mediates C6-ceramide-induced cell death in chronic lymphocytic leukemia

Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway

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