Heat‐shock protein 27 (HSP27, HSPB1) is synthetic lethal to cells with oncogenic activation of MET, EGFR and BRAF

• Published in: Molecular oncology 2017-06, Vol.11 (6), p.599-611
• Main Authors: Konda, John D., Olivero, Martina, Musiani, Daniele, Lamba, Simona, Di Renzo, Maria F.
• Format: Article
• Language: English
• Subjects: Addictions; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; c-Met protein; Cancer; Cancer therapies; Caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Cell activation; Cell cycle; Cell Cycle - drug effects; Cell death; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation - drug effects; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Cytotoxicity; Development and progression; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gastric cancer; Gene expression; Gene Knockdown Techniques; Genetic aspects; Heat shock proteins; HEK293 Cells; HSP27 Heat-Shock Proteins - genetics; HSP27 Heat-Shock Proteins - metabolism; Hsp27 protein; Humans; Immunoglobulins; Kinases; Lamin B Receptor; Lung cancer; Medical prognosis; Melanoma; Metastases; Mitochondria; Mitochondria - metabolism; Molecular Chaperones; Molecular Targeted Therapy; Mutation; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Oncogene Addiction; oncogenes; Prostate; Proteins; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA Interference; RNA, Small Interfering - genetics; small heat‐shock proteins; Stem cells; target therapy; Tumor cell lines; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12042

The small heat‐shock protein of 27 kDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumour behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene‐addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET‐addicted EBC‐1 lung cancer cells, epidermal growth factor receptor (EGFR)‐addicted colorectal carcinoma (CRC) DiFi cells and BRAF‐addicted CRC COLO205 and OXCO‐1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent. In other cell lines, such as MET‐addicted gastric carcinoma MKN45 and EGFR‐addicted CRC SW48 lines, where oncogene inhibition only blocked proliferation, HSP27 knockdown made targeted agents switch from cytostatic to cytotoxic activity. Mechanistically, the more the cells were susceptible to HSP27 suppression, the more they were primed for death, as demonstrated by increased levels of mitochondrial outer membrane permeabilization. Priming for death was accompanied by the increase in pro‐apoptotic proteins of the BCL2 family and of active caspase‐3 and lamin B. Together, these data suggest that oncogene‐addicted cells require HSP27 for survival and that HSP27 might interfere with the effectiveness of targeted agents. Knockdown of the small heat‐shock protein HSP27 triggers apoptosis in cancer cells with oncogene overactivation and converts cytostatic targeted agents into fully cytotoxic drugs. HSP27 suppression results in increased mitochondrial membrane permeabilization due to modulation of BCL2 proteins and primes cells for apoptosis. Thus, increased expression of HSP27 in cancer might interfere with the effectiveness of targeted therapies.