Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75

Mediavilla-Varela, Melanie; Pacheco, Fabio J.; Almaguel, Frankis; Perez, Jossymar; Sahakian, Eva; Daniels, Tracy R.; Leoh, Lai Sum; Padilla, Amelia; Wall, Nathan R.; Lilly, Michael B.; León, Marino De; Casiano, Carlos A.

doi:10.1186/1476-4598-8-68

Cited by 108 publications

(107 citation statements)

References 49 publications

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“…In a previous study we reported that LEDGF/p75 overexpression in PCa cells promoted resistance against caspase-independent cell death induced through lysosomal membrane permeabilization (LMP) by the taxane drug docetaxel (DTX), the gold standard for advanced PCa chemotherapy [18]. These results were consistent with studies in other cancer cell types demonstrating that LEDGF/p75 overexpression promoted cellular protection against LMP-inducing drugs [19].…”

Section: Introductionsupporting

confidence: 75%

Targeting the stress oncoprotein LEDGF/p75 to sensitize chemoresistant prostate cancer cells to taxanes

et al. 2017

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Prostate cancer (PCa) is associated with chronic prostate inflammation resulting in activation of stress and pro-survival pathways that contribute to disease progression and chemoresistance. The stress oncoprotein lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, promotes cellular survival against environmental stressors, including oxidative stress, radiation, and cytotoxic drugs. Furthermore, LEDGF/p75 overexpression in PCa and other cancers has been associated with features of tumor aggressiveness, including resistance to cell death and chemotherapy. We report here that the endogenous levels of LEDGF/p75 are upregulated in metastatic castration resistant prostate cancer (mCRPC) cells selected for resistance to the taxane drug docetaxel (DTX). These cells also showed resistance to the taxanes cabazitaxel (CBZ) and paclitaxel (PTX), but not to the classical inducer of apoptosis TRAIL. Silencing LEDGF/p75 effectively sensitized taxane-resistant PC3 and DU145 cells to DTX and CBZ, as evidenced by a significant decrease in their clonogenic potential. While TRAIL induced apoptotic blebbing, caspase-3 processing, and apoptotic LEDGF/p75 cleavage, which leads to its inactivation, in both taxane-resistant and -sensitive PC3 and DU145 cells, treatment with DTX and CBZ failed to robustly induce these signature apoptotic events. These observations suggested that taxanes induce both caspase-dependent and -independent cell death in mCRPC cells, and that maintaining the structural integrity of LEDGF/p75 is critical for its role in promoting taxane-resistance. Our results further establish LEDGF/p75 as a stress oncoprotein that plays an important role in taxane-resistance in mCRPC cells, possibly by antagonizing drug-induced caspase-independent cell death.

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Section: Introductionsupporting

confidence: 75%

Targeting the stress oncoprotein LEDGF/p75 to sensitize chemoresistant prostate cancer cells to taxanes

et al. 2017

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“…Unusually, high expression of LEDGF promotes cell survival, and may initiate cellular abnormalities or promote tumor formation. 6,65,66 Low expression leads to negative regulation of survival signaling. Recent studies have investigated various features of LEDGF protein, regulation of its gene and its role in cancer and HIV.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic repression of LEDGF during UVB exposure by recruitment of SUV39H1 and HDAC1 to the Sp1-responsive elements within LEDGF promoter CpG island

et al. 2013

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“…6A). In prostate cancer cells, docetaxel-induced cell death involves the processing of caspases, particularly the executioner caspase-3, an event associated with the activation of PARP, a canonical caspase-3 substrate (29). In scrambled RNAi-transfected PC-3, a diminution of both 32 kDa unprocessed caspase-3 and 116 kDa unprocessed PARP expression during treatment with docetaxel was found (Fig.…”

Section: Chemotherapy-induced Cell Death Is Inhibited By Spl Knockdowmentioning

confidence: 94%

First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer

Brizuela

Ader

Mazerolles

et al. 2012

Molecular Cancer Therapeutics

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This is the first report of sphingosine 1-phosphate lyase (SPL) protein expression and enzymatic activity in human neoplasm. This enzyme drives irreversible degradation of sphingosine 1-phosphate (S1P), a bioactive lipid associated with resistance to therapeutics in various cancers, including prostate adenocarcinoma. In fresh human prostatectomy specimens, a remarkable decrease in SPL enzymatic activity was found in tumor samples, as compared with normal adjacent tissues. A significant relationship between loss of SPL expression and higher Gleason score was confirmed in tissue microarray (TMA) analysis. Moreover, SPL protein expression and activity were inversely correlated with those of sphingosine kinase-1 (SphK1), the enzyme producing S1P. SPL and SphK1 expressions were independently predictive of aggressive cancer on TMA, supporting the relevance of S1P in prostate cancer. In human C4-2B and PC-3 cell lines, silencing SPL enhanced survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. In contrast, enforced expression of SPL sensitized cancer cells to irradiation or docetaxel by tilting the ceramide/S1P balance toward cell death. Interestingly, the S1P degradation products failed to sensitize to chemo-and radiotherapy, supporting the crucial role of ceramide/ S1P balance in cancer. Of note, the combination of SPL enforced expression with a SphK1 silencing strategy by further decreasing S1P content made prostate cancer cells even more sensitive to anticancer therapies, suggesting that a dual strategy aimed at stimulating SPL, and inhibiting SphK1 could represent a future approach to sensitize cancer cells to cancer treatments.

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Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75

Cited by 108 publications

References 49 publications

Targeting the stress oncoprotein LEDGF/p75 to sensitize chemoresistant prostate cancer cells to taxanes

Targeting the stress oncoprotein LEDGF/p75 to sensitize chemoresistant prostate cancer cells to taxanes

Epigenetic repression of LEDGF during UVB exposure by recruitment of SUV39H1 and HDAC1 to the Sp1-responsive elements within LEDGF promoter CpG island

First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer

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