Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

Cytotoxic chemotherapies act by triggering cell death in tumor cells. Expression of NMI sensitized breast cancer cell lines to DNA damaging agents, such as doxorubicin and cisplatin. 33 Autophagy, occasionally termed programmed cell death II, was implicated in the enhanced sensitivity imparted by NMI. NMI expression in NMI deficient cell lines elevated basal levels of autophagy in breast cancer cell lines, as indicated by autophagic vacuole formation. This was confirmed molecularly by LC3 processing and expression of Beclin, and p62. 33 In certain cellular contexts, autophagy enables cell survival under conditions of stress. However, activation of autophagy beyond a threshold leads to extensive autodigestion and subsequent cell death. 34 Numerous novel cancer treatment strategies aim to induce autophagic cell death. 35 In the context of clinical specimens, NMI expression significantly correlated with the expression of DNA-damage regulated autophagy mediator 1(DRAM1) mRNA in breast tumors collected by the Cancer Genome Atlas. 33 DRAM1 is essential for the final steps of autophagy and mediates the fusion of autophagosomes with lysosomes. 36 Experimentally, decreasing DRAM1 expression in MDA-MB-231 breast cancer cells expressing NMI protected the cells against cisplatin treatment. 33 Furthermore, Crighton et al. showed that DRAM1 induction of autophagy is essential for p53-mediated cell death. 37 In this study, combinatorial knock down of ATG5 and DRAM1 did not additively affect apoptosis, suggesting that both proteins act through the same cell death pathway-autophagy. Taken together these findings point out that NMI imparts chemosensitivity by enhancing autophagic cell death.