Autophagy delays apoptotic death in breast cancer cells following DNA damage

Abstract

Early signaling in camptothecin-treated MCF-7 cells followed an intrinsic pathway, but death was delayed and late events exhibited few hallmarks of apoptosis. BH3-only proteins, such as Noxa, Puma and BimEL, were activated and localized to mitochondrial sites within 24 h following drug exposure. However, caspase activity was low and death was unaffected by caspase inhibition. Transmission electron micrographs showed the presence of large vacuoles in drug-treated cells. An autophagic survival response has been attributed to MCF-7 cells following nutrient starvation or exposure to tamoxifen. Here, we show that autophagy also plays an important role in the delayed DNA damage response. Confocal microscopy revealed colocalization of mitochondria with large autophagic vacuoles and inhibitors of autophagy increased mitochondrial depolarization and caspase-9 activity, and accelerated cell death. Furthermore, downregulation of autophagy proteins, Beclin 1 and Atg7, unmasked a caspase-dependent, apoptotic response to DNA damage. We propose that a post-mitochondrial caspase cascade is delayed as a result of early disposal of damaged mitochondria within autophagosomes. Our data also suggest that the use of autophagy as a means of delaying apoptosis or prolonging survival may be characteristic of noninvasive breast tumor cells. These studies underscore a potential role for autophagy inhibitors in combination with conventional chemotherapeutic drugs in early breast cancer therapy.

Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development

“…17,18 A series of studies reported that chemotherapy induced-autophagy promotes the survival of some kinds of cancer cell lines. [19][20][21][22][23] These results suggest that autophagy might be involved in the development of chemotherapy resistance. But few studies on the relationship between autophagy and chemotherapy were reported, especially studies utilizing resistant cancer cells.…”

“…Consistent with previous studies, we found that MMP was damaged within 24 h when MCF-7 cells were treated with EPI, whereas caspase-9 activity did not increase dramatically. 19,35,36 Accordingly, only a few cells underwent intrinsic apoptosis, and the cells exhibited caspase-independent death. Interestingly, MCF-7 cells underwent autophagy when treated with EPI.…”

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

“…We observed that autophagy was enhanced by etoposide. The upregulation of autophagy by chemotherapeutic drugs has already been described [42][43][44][45][46][47]. Chemotherapyinduced autophagy may promote cell resistance against it.…”

“…Doxorubicin-induced DNA damage stimulates cytoprotective autophagy through a PARP-1-dependent pathway [48]. Similarly, cisplatin-induced autophagy delays apoptosis in renal tubular epithelial cells [45] and tamoxifen and camptothecin-induced autophagy increases MCF7 breast carcinoma cell line viability [42,46]. Examples of autophagic cell death in response to chemotherapy were also described.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…Hypoxic AKT suppression was associated with a decrease in cell proliferation and induction of autophagy [59], playing an important role in enhancing cell viability in adverse conditions [60,61]. These observations show the plasticity of invasive and proliferative tumor states, which can be mediated by the convergence of hypoxia and MET signaling pathways.…”