Smac mimetic-induced caspase-independent necroptosis requires RIP1 in breast cancer

Abstract

There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial‑derived activator of caspase/direct IAP‑binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA‑MB‑231 and MCF‑7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161‑dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor‑interacting protein kinase‑1 via small interfering RNA protected the cells from LCL161‑induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds.

Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy

“…[ 222 ] have shown that necroptosis and PARP-1-mediated necrotic cell death follow two distinct routes to regulate necrosis. In addition, small molecule inhibitors that antagonize inhibitors of apoptotic proteins, such as second mitochondrial activator of caspases (smac) mimetics, were shown to cause necroptotic cell death in fibrosarcoma cells, breast cancer cells, and acute lymphoblastic leukemia, underscoring the potential clinical relevance of this therapeutic strategy [ 223 – 224 ], which is regulated by ROS [ 225 ]. Therefore, whether cancer cells undergo apoptosis or necroptosis following exposure to smac mimetics will be crucial for the implementation of therapy, and should be addressed in future studies.…”

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“…In cases of cellular stress, if there is no functional caspase-8 or if RIP1 is not ubiquitinated, the cell undergoes necroptosis [36]. In a study conducted on MDA-MB-231 and MCF-7 breast cancer cells, it was thought that RIP1 accumulated due to the destruction of cIAP by a SMAC mimetic, and therefore necroptosis occurred [37].…”

Bivalent SMAC Mimetics for Treating Cancer by Antagonizing Inhibitor of Apoptosis Proteins

“…It may also allow SMAC mimetics to promote cell death synergistically through both necroptotic and apoptotic processes. These possibilities should be investigated systematically in different cell types, since SMAC mimetic‐induced initiation of necroptosis has so far been observed only in colon cancer cells, ovarian cancer cells, leukemia cells, and breast cancer cells …”

“…These possibilities should be investigated systematically in different cell types, since SMAC mimetic-induced initiation of necroptosis has so far been observed only in colon cancer cells, [96] ovarian cancer cells, [94] leukemia cells, [96,97] and breast cancer cells. [98] The preceding discussion has focused on using bivalent SMAC mimetics by themselves as monotherapy. They can also be administered in combination with other kinds of anticancer drugs or therapies to sensitize apoptosis-resistant cancer cells.…”