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

Abstract

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.

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

“…Our group also demonstrated that ectopic overexpression of DFS70/ LEDGF in PCa cells is associated with upregulation of specific stress and antioxidant proteins as well as resistance to non-apoptotic cell death induced by chemotherapy and oxidative-stress [26,30,31,81]. More recent studies from our laboratory demonstrated that PCa cells selected for chemotherapy resistance activate a cancer stem cell transcriptomic program that is associated with upregulation of DFS70/LEDGF and other related proteins, and that knockdown of this protein via siRNA in these cells re-sensitizes them to taxane-based chemotherapy [82,83]. Consistent with these results, several other groups have provided evidence that DFS70/LEDGF is also overexpressed in other cancer types, and various studies with ectopic overexpression and siRNA-mediated knockdown have shown that this protein promotes features of tumor aggressiveness, including cell proliferation, migration, invasion, clonogenicity, tumor growth, angiogenesis, DNA repair, and chemoresistance [24,25,27,55,[84][85][86][87][88][89].…”

Glucocorticoids Induce Stress Oncoproteins Associated with Therapy-Resistance in African American and European American Prostate Cancer Cells

“…Our group and others have demonstrated that LEDGF/p75 is a stress response transcription co-activator upregulated in PCa as well as other cancers that promotes cellular survival in the presence of chemotherapeutic drugs and radiation 27 , 28 , 38 – 45 . While CLU inhibits drug-induced apoptosis by preventing mitochondrial membrane permeabilization 20 , 22 , 23 , LEDGF/p75, acting as a stress transcription co-activator, transactivates stress response and anti-oxidant genes, and promotes resistance to oxidative stress-induced necrosis and DTX-induced caspase-independent lysosomal cell death 27 , 28 , 38 , 39 . In a recent study, we showed that depletion of LEDGF/p75 in DTX-resistant mCRPC cells partially resensitized the cells to DTX treatment 28 .…”

“…We hypothesized that stress oncoproteins that are upregulated in the context of standard PCa treatments and that promote therapy resistance may be upregulated by GR signaling. As a first step in evaluating this hypothesis we focused on the contribution of GR signaling to the expression of the stress oncoproteins Clusterin (CLU) and Lens Epithelium-Derived Growth Factor p75 (LEDGF/p75), previously shown to be upregulated in response to standard PCa therapies, including taxane therapy 18 – 28 . CLU is an AR-regulated, anti-apoptotic protein that is upregulated in PCa, particularly following ADT, as well as several other cancers 19 , 21 , 23 , 24 , 29 – 35 .…”

“…While CLU inhibits drug-induced apoptosis by preventing mitochondrial membrane permeabilization 20 , 22 , 23 , LEDGF/p75, acting as a stress transcription co-activator, transactivates stress response and anti-oxidant genes, and promotes resistance to oxidative stress-induced necrosis and DTX-induced caspase-independent lysosomal cell death 27 , 28 , 38 , 39 . In a recent study, we showed that depletion of LEDGF/p75 in DTX-resistant mCRPC cells partially resensitized the cells to DTX treatment 28 . Further, other groups have shown that downregulation of LEDGF/p75 reduced cancer cell proliferation, migration, tumorigenicity, and sensitized cancer cells to anti-tumor drugs 46 – 49 .…”

Natriuretic Peptides: The Case of Prostate Cancer

“…It has been reported [ 93 ] that the infiltration of macrophages and immune suppressor cells is positively associated with PCa progression, since the infiltrating lymphocytes and the tumor-microenvironment, by secreting large amounts of cytokines/chemokines, trigger a vicious circle, which drives cellular activities to cancer progression and aggressiveness [ 102 , 103 , 104 , 105 ]. In general, although prostate cancer, as well as each type of human cancers, is characterized by a multistep development, targeting the chronic inflammation branch could have potential beneficial effects for the treatment of this deadly neoplasia [ 62 , 106 , 107 ].…”