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Oprozomib (Cpd 21) was chosen for the subsequent experiments. The isobaric tags for relative and absolute quantitation (iTRAQ) was then performed to identify the responsible pathway relative to apoptosis and the results showed that endoplasmic reticulum (ER) chaperones were upregulated. Apoptosis was attributed to a joint effect of calcium leakage andPERK and IRE1\u03b1 phosphorylation. The PERK branch was responsible for the first wave of cell death that occurred within 24\u00a0hours. The later wave of apoptosis was mediated by IRE1\u03b1, which transmit apoptotic signals through the ASK\u2010JNK\u2010BIM axis. Release of Ca2+ from ER into cytosol resulted in activation of calpain, which, in turn, cleaved caspase\u201012. Our data also explained the selective killing effects of oprozomib on CML cells, which relied on proteasome activity. The present study demonstrated that prolonged inhibition of proteasome to trigger unfolded protein response could be an alternative strategy for treating CML in light of tyrosine kinase inhibitors resistance.<\/jats:p>","DOI":"10.1111\/cas.14696","type":"journal-article","created":{"date-parts":[[2020,10,17]],"date-time":"2020-10-17T08:46:15Z","timestamp":1602924375000},"page":"133-143","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Prolonged unfolded protein reaction is involved in the induction of chronic myeloid leukemia cell death upon oprozomib treatment"],"prefix":"10.1111","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3538-9661","authenticated-orcid":false,"given":"Fang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine The First Affiliated Hospital of Xi\u2019an Jiaotong University Xi\u2019an 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