Organic killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity. of drugs that do not affect cell vitality are indicatedHSF1 activation (37) and, with a similar mechanism, MICA and MICB expression on MM cells is usually enhanced by HSP90 chaperone inhibitors that activate this transcription factor (21). In a different way, increased surface expression of the mouse NKG2D ligand Mult1 depends on the inhibition of protein ubiquitination and lysosomal degradation (38). Treatment of different tumor cell types with epigenetic drugs, like histone deacetylase inhibitors (HDACi) and DNA-methyltransferase inhibitors (DNMTi) (25C27, 39C43), leads to the upregulation of NKG2DLs and PVR surface levels, although it downregulates B7-H6 expression (44). For DNMTi the molecular mechanisms underlying NKG2DLs upregulation are still unclear, while different pathways cooperate in the regulation of these molecules in response to HDACi, and this might depend on the type of tumor and the dose of the drug used. In particular, valproic acid (VPA) has been reported to upregulate MICA/B with a mechanism dependent on PI3K/Akt pathway in pancreatic cancer cells (40), while the involvement of ERK in MICA/B and ULBP2 upregulation in response to VPA has been shown in MM cells (45). Moreover, Yang and colleagues proposed that the capability of the HDACi suberoylanilide-hydroxamic acid (SAHA) to increase MICA expression in hepatoma cancer cells is dependent on miR-17-92 cluster (46). In MM cells, the bromodomain and extra terminal domain name inhibitors (BETi) and immunomodulatory drugs (IMiDs) can block the repressive activity Rabbit polyclonal to NGFRp75 of the transcription factors IRF4 and IKZF1/3 on MICA and PVR promoters (19, 47). In addition, both these therapeutic brokers can downregulate the expression of PD-L1 on cancer cells (28, 29, 31, 32). Indeed, BETi interrupt the activity of the epigenetic reader protein BRD4 on PD-L1 promoter region, by considerably reducing both constitutive and IFN- inducible appearance of the ligand. In this respect, the downstream mediators of IFN- signaling, JAK kinases, could be pharmacologically obstructed to adversely regulate PD-L1 appearance in tumor cells (48). Furthermore, medications disrupting RAF/MEK/ERK signaling pathway, such as for example SCH900776 (S-isomer) Sorafenib as well as the TLR3 agonists poly-IC, can synergistically decrease the percentage of tumor cells expressing PD-L1 and enhance NK and T cell activation within a mouse style of hepatocarcinoma (49). Relating to medications that disrupt the microtubule set up, sub-lethal dosages of Vincristine can activate p38 MAPK and regulate NKG2DL appearance both at transcriptional and posttranscriptional level in MM cells (50). Furthermore, Cytochalasin D, nocodazole, and docetaxel can boost NKG2D, DNAM-1, and NKp30 ligands on tumor cell surface, with MICA upregulation being dependent on both DNA damage and endoplasmic reticulum SCH900776 (S-isomer) (ER) stress response (51). Different studies have been done by using proteasome inhibitors in MM cells. In this regard, low doses of bortezomib can induce the upregulation of both NKG2D and DNAM-1 ligands (22, 52, 53), and in accordance with these data, Jinushi and colleagues reported a DDR-ATM-dependent upregulation of MICA surface levels (24). On the other hand, no significant change in NKG2DL expression was observed upon bortezomib treatment by Shi and colleagues (30). Interestingly, the latter study described the capability of bortezomib to downregulate HLA class I surface expression by sensitizing MM cells to NK cellCmediated lysis (30). Chemotherapeutic brokers can also contribute to the posttranslational regulation of NK activating SCH900776 (S-isomer) ligand expression by promoting the release of soluble NKG2DLs through the modulation of the expression and activity of metalloproteinases (MMP) and ADAM enzymes on cancer cells (54). Although an increased stimulation of the shedding process in response to genotoxic brokers has been reported (55), some studies using different drugs describe an.