Acid ceramidase‐mediated production of sphingosine 1‐phosphate promotes prostate cancer invasion through upregulation of cathepsin B

Beckham, Thomas H.; Lü, Ping; Cheng, Joseph; Zhao, Daqing; Turner, Lorianne S.; Zhang, Xiaoyi; Hoffman, Stanley; Armeson, Kent; Liu, Angen; Marrison, Tucker; Hannun, Yusuf A.; Liu, Xiang

doi:10.1002/ijc.27480

Cited by 56 publications

(46 citation statements)

References 24 publications

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“…Both ASAH1 and Akt2 have individually been implicated in cell invasion via distinct mechanisms, 20,[32][33][34] raising the question whether these two enzymes cooperate to induce cell invasion. To address this question, we transfected immortalized, non-transformed HPNE cells with ASAH1 and Akt2, either alone or together, and determined their effects on cell invasion as described in "Materials and Methods."…”

Section: Resultsmentioning

confidence: 99%

“…[9][10][11] Furthermore, Akt was shown to promote invasiveness by upregulating the expression of IGF-1 receptor, β1-integrin and MMP-9, respectively, 20,33,34 whereas ASAH1 was shown to promote proliferation and survival by affecting retinoblastoma protein (RB) phosphorylation 41 and Bax levels, 42 and to stimulate invasion by upregulating cathepsin B. 32 In addition, there may be crosstalk between ASAH1 and Akt-regulated pathways. For example, ASAH1 increases cellular sphingosine-1 phosphate, which was previously shown to activate Akt.…”

Section: Resultsmentioning

confidence: 99%

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Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Berndt¹,

Patel²,

Yang³

et al. 2013

Cell Cycle

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Berndt¹,

Patel²,

Yang³

et al. 2013

Cell Cycle

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“…Cathepsin B overexpression has been demonstrated to attribute to the invasive and metastatic potential of malignancies, e.g. in pancreatic and prostate cancer [41,42]. In adenocarcinomas of the gastro-esophageal junction, increased Cathepsin B activity was found to correlate with lymph node involvement [6].…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Verbeek

Siersema

Vleggaar

et al. 2016

JGLD

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Background & Aims: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett’s esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett’s esophagus epithelium cell line. Methods: TLR2 expression in normal squamous esophagus, reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma biopsies was assessed with Q-RT-PCR, in situ hybridization and immunohistochemistry. Barrett’s esophagus epithelium cells (BAR-T) were incubated with acid and bile salts in the presence or absence of the TLR2 agonist Pam3CSK4 for a period up to 4 weeks. Morphological changes were assessed with electron microscopy, while Q-RT-PCR was used to determine the expression of lysosomal enzymes (Cathepsin B and C) and factors involved in endocytosis (LAMP-1 and M6PR) and autophagy (LC3 and Rab7). Results: TLR2 was expressed in normal squamous esophagus, reflux esophagitis, Barrett’s esophagus but was most prominent in esophageal adenocarcinoma. Long-term TLR2 activation in acid and bile salts exposed BAR-T cells resulted in more and larger lysosomes, more mitochondria and increased expression of LAMP-1, M6PR, Cathepsin B and C when compared to BAR-T cells incubated with acid and bile salts but no TLR2 agonist. Factors associated with autophagy (LC3 and Rab7) expression remained largely unchanged. Conclusion: Activation of TLR2 in acid and bile salts exposed Barrett epithelium cells resulted in an increased number of mitochondria and lysosomes and increased expression of lysosomal enzymes and factors involved in endocytosis. Abbreviations: BE: Barrett’s esophagus; DCA: deoxycholic acid; EAC: esophageal adenocarcinoma; GCA: glycocholic acid; IL8: interleukin 8; IHC: immunohistochemistry; ISH: in situ hybridization; LAMP-1: lysosomal-associated membrane protein-1; LC3: microtubule-associated protein 1A/1B-light chain 3; M6PR: mannose-6-phosphate receptor; NF-κB: Nuclear Factor–κB; PPIs: proton pump inhibitors; Q-RT-PCR: Quantitative reverse transcriptase polymerase chain reaction; RE: reflux esophagitis; SQ: normal squamous esophagus; TCDCA: taurochenodeoxycholic acid; TLR: Toll-like receptor; TNFα: tumor necrosis factor α.

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“…tive approach to studying AC in cancer cells, as their enhanced autophagy and secretory activity enriches the extracellular concentration of lysosomal contents (102)(103)(104) and because AC can be detected and isolated from human urine (105).…”

Section: Discussionmentioning

confidence: 99%

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

et al. 2013

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Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

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Acid ceramidase‐mediated production of sphingosine 1‐phosphate promotes prostate cancer invasion through upregulation of cathepsin B

Cited by 56 publications

References 24 publications

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

Toll-like Receptor 2 Signalling and the Lysosomal Machinery in Barrett’s Esophagus

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

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