Table 2.
Pre-clinical studies with ER stress response factors in other solid tumours and haematological malignancies.
| Factor | Disease | Material | Treatment (Concentration) | ER Stress Factors Involved | p | Brief | Ref |
|---|---|---|---|---|---|---|---|
| ATF4 | Pancreatic neuroendocrine tumour | 45 patient samples | - | GRP78/ATF4/CHOP | <0.05 | ATF4 is overexpressed in pancreatic neuroendocrine tumours | [75] |
| MCL and AML | MCL cell lines (Z-138, JVM-2, MINO, and JeKo-1). AML cell lines (OCI-AML3, MOLM-13, HL-60, and THP-1). Primary cells. Mouse models (via tail vein injection) | ONC201 (5 μm), rapamycin (10 nm), or tunicamycin (1 μm) | ATF4/mTORC1 | <0.0001 | ONC201 induces apoptosis independent of TP53 mutation status and causes changes in gene expression similarly by UPR. ONC201 induces ATF4 and inhibits mTORC1 | [71] | |
| ATF4-ATF3-CHOP | TLL | TLL cell lines (Jurkat, Molt4) and the T-cell hybridoma cell line (DO11.10) | Farnesol (75 μm) | ATF4/ATF3/CHOP/PERK-eIF2α | <0.01 | Farnesol induces apoptosis in leukemic cells by induction of the PERK-eIF2α-ATF3/4 cascade | [72] |
| ATF4 | CRC | CRC cell lines (HCT116 and LoVo) | Glucose deprivation (1,5 mmol/L glucose) | GRP78/PERK/ATF4 | <0.001 | Glucose deprivation protects cells from oxaliplatin- and 5-fluorouracil-induced apoptosis, and induces the expression of ATF4. Depletion of ATF4 can induce apoptosis and drug re-sensitisation. | [73] |
| ATF6 | Insulinoma | Cell lines isolated from rat and mouse pancreas (INS-1 832/13) | Tunicamycin (0.1 µg/m), thapsigargin (0.1 µg/m), staurosporin, SB239063 (50 µm), and SP600125 (50 µm), ATF6α siRNA | GRP78/ATF6α | <0.05 | ATF6α knockdown activates JNK and P38 to induce apoptosis in insulinoma cells and primary islets | [90] |
| OC and CML | OC cell lines (HeLa), and CML cell lines (K562 and LAMA) | Dithiothreitol (1 mm), thapsigargin (500 nm), azetidine-2-carboxylic acid (10 mm), and tunicamycin (5 μg/mL) | PDIA5/ATF6/BiP | <0.01 | PDIA5/ATF6α axis modulates sensitivity of leukemia cells to imatinib | [92] | |
| IRE1α | AML | AML cell lines (NB4, U937, K-562, TF-1, HL-60, PL-21, and THP-1). Primary samples and murine hematopoietic cells | 2-hydroxy-1-naphthaldehyde (25 μm), STF-083010 (50 μm), and toyocamycin (500 nm) | IRE1α/XBP1 | <0.01 | Inhibition of IRE1α decreases cell viability and induces apoptosis and G1 cell cycle arrest | [81] |
| IRE1/ATF6 | Melanoma | Melanoma cell lines (Mel-RM, Mel-RMu, Mel-CV, and MM200) | siRNA and shRNA of IRE1α and ATF6 | IRE1α/ATF6 | <0.05 | IRE1α and ATF6 are critical for survival of melanoma cells undergoing ER stress | [93] |
| IRE1/XBP1 | BC | BC cell lines (MDA-MB-231 and MCF-7) | Thapsigargin (250 nm) or bortezomib (100 nm) | IRE1/XBP-1 | <0.05 | Estrogen receptor β sensitises BC cells to thapsigargin and to bortezomib by regulating the IRE1/XBP-1 pathway | [83] |
| BC | BC cell lines (SUM159, BT549, and MDA-MB-231), PDX models, and genetically engineered mouse models | Small molecule inhibitor 8866 (300 mg/kg oral daily) | IRE1/XBP1 pathway and MYC | <0.001 | Silencing of XBP1 selectively blocks the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 selectively restrained MYC-overexpressing tumour growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models | [84] | |
| XBP-1 | BC | CSC derived from MCF7 cell line (CD44+/CD24-) | Tunicamycin (2 μg/mL) | XBP-1/ATF6/CHOP | <0.001 | Tunicamycin inhibited invasion, increased cell death, suppressed proliferation, and reduced migration in a CD44+/CD24- and CD44+/CD24- rich MCF7 cell culture by an increased level of spliced XBP-1, ATF6 nuclear translocation and CHOP protein expression | [77] |
| P38α/β | CRC and BC | CRC cell lines (HT29, HCT116, and LS174T) and BC cell lines (MDA-MB-231) | Heparan sulfate hexasaccharide (100 µm) | TCF4 | <0.005 | Heparan sulfate hexasaccharide selectively inhibits CSC self-renewal and induces apoptosis in colorectal and breast CSCs | [97] |
| GRP78 | CRC | CRC cell lines (HT29, HT8, SW480 and colo205) | Oxaliplatin (5 µm) and vomitoxin (1 µg/mL) | GRP78/CD24 | <0.001 | Suppression of GRP78 sensitises human colorectal cancer cells to oxaliplatin by downregulation of CD24 | [62] |
| BC | BC cell lines (MCF-7 and T47D) | Plumbagin (from 0.5 to 5 μm) and Tamoxifen (1 or 5 μm) | GRP78/BIK | < 0.05 | Plumbagin inhibits GRP78 activity, and increases Bik expression and apoptosis induction, which contributes to the sensitisation of BC cells to tamoxifen | [63] | |
| NSCLC and GB | NSCLC cell lines (A549, and H460), and GB cell lines (D54 and U251). Mouse xenografts. | Anti-GRP78 antibody (1 μg/mL) | GRP78 and PI3K/AKT/mTOR signaling | <0.0001 | Anti-GRP78 attenuates cell proliferation, enhances radiation therapy, induces apoptosis, and delays tumour growth in mouse xenograft through the suppression of Akt/mTOR signaling | [64] | |
| PERK | Insulinoma | Mice samples (insulinoma generated by SV40 Large T-Antigen) | ISRIB (250 nm), Gemcitabine (1 μm), ATF4 siRNA | PERK | <0.000005 | PERK promotes tumour proliferation and angiogenesis | [68] |
| Breast, lung and gastric cancer | BC cell lines (MCF7, T47D, BT474, BT549, ZR-75–30, Hs578T, MDA-MB-157, and MDA-MB-231). Orthotopic injection into a mammary pad on NOD/SCID mice. Breast, lung and gastric cancer patient samples. | AEBSF (1 mg) | PERK/CREB3L1/ATF4 | < 0.01 | PERK signalling drives invasion and metastasis of breast cancer cell lines through CREB3L1, and associates with a poor outcome in breast, lung, and gastric cancer patients | [69] |
AML: acute myeloid leukemia; BC: Breast cancer; CML: chronic myeloid leukemia; CSC: Cancer stem cell; CRC: Colorectal cancer; EC: endometrial cancer; ER: endoplasmic reticulum; GB: Glioblastoma; NOD/SCID: non-obese diabetic/severe combined immunodeficiency; NSCLC: non-small cell lung cancer; MCL: mantle cell lymphoma; OC: Ovarian Cancer; PDX: patient-derived xenograft; TLL: T lymphoblastic leukemia; UPR: unfolded protein response; Ref: references.