PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1

Abstract

Most deaths from breast cancer result from tumour recurrence, which is typically an incurable disease. Down-regulation of the pro-apoptotic tumour suppressor protein prostate apoptosis response-4 (PAR-4) is required for breast cancer recurrence and resistance to chemotherapy. Recent advances in the analysis of apoptotic signalling networks have uncovered an important role for activation of caspase-8 following DNA damage by genotoxic drugs. DNA damage induces depletion of IAP proteins and causes caspase-8 activation by promoting the formation of a cytosolic cell death complex. We demonstrate that loss of PAR-4 in triple negative breast cancer cell lines (TNBC) mediates resistance to DNA damage-induced apoptosis and prevents activation of caspase-8. Moreover, loss of PAR-4 prevents DNA damage-induced cIAP1 depletion. PAR-4 functions downstream of caspase-8 by cleavage-induced nuclear translocation of the C-terminal part and we demonstrate that nuclear translocation of the C-terminal PAR-4 fragment leads to depletion of cIAP1 and subsequent caspase-8 activation. Specifically targeting cIAP1 with RNAi or Smac mimetics (LCL161) overcomes chemo-resistance induced by loss of PAR-4 and restores caspase-8 activation. Our data identify cIAP1 as important downstream mediator of PAR-4 and we provide evidence that combining Smac mimetics and genotoxic drugs creates vulnerability for synthetic lethality in TNBC cells lacking PAR-4.

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

“…The evidence that Par-4 is important for cell death in many cancer cell types is mounting. Par-4 is increased in response to agents that are in the clinic, viz; 5-FU 47 , 114 , doxorubicin 5 , etoposide 70 , and radiotherapy 46 . Indeed, a large variety of anticancer agents have been identified that can effectively activate Par-4 and eliminate cancer cells (Table 2 ).…”

“…Later, Treude et al demonstrated that caspase-8 also generates cl-Par-4 in response to TNFαand UV-induced apoptosis 67 . Indeed, cl-Par-4 was generated in response to a variety of anticancer agents effectively eliminating the cancer cells 33,34,[67][68][69][70] .…”

Differential effects of alliin and allicin on apoptosis and senescence in luminal A and triple‐negative breast cancer: Caspase, ΔΨm, and pro‐apoptotic gene involvement

“…This JC-10 staining is capable of selectively entering mitochondria and shifts its fluorescence emission color from green to orange as membrane potentials increase. MCF-7 (5 9 10 3 ) or HCC-70 (1 9 10 4 ) cells were seeded into 96-well plates in 100 µL of medium and were incubated at 37°C for 4 h. MCF-7 and HCC-70 cells were treated with alliin (10 or 1 000 lM) or allicin (9,12,20, or 45 lM) for 24 h. After the treatment, as described by the manufacturer, the cells were stained with JC-10 solution. Fluorescence was measured at ex/em: 530/590 nm in a plate reader (Synergy).…”

“…Many chemo-and radiotherapy target pathways are involved in cell death. However, some tumor cells evolve a variety of strategies to limit or circumvent apoptosis, therefore acquiring chemoresistance [9]. For example, cancer cells do not respond to intrinsic (p53, Rb) [10] or extrinsic regulatory mechanisms (induction of apoptosis via caspase-8) [11].…”

Pentagalloyl glucose inhibits TNF‐α‐activated CXCL1/GRO-α expression and induces apoptosis‐related genes in triple-negative breast cancer cells

“…However, it is well-known that chemotherapeutic resistance in BC is associated with abnormal growth factor signaling and aberrant hormonal response. The exact mechanisms of this phenomenon in cancer treatment are still unknown 1 , 2 . Current insights in molecular targets lead to the recognition of BC therapy in the subset HER2/neu.…”