Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and -resistant chronic myeloid leukemia cells

Abstract

Development of drug resistance due to BCR-ABL point mutations and the persistence of leukemia initiating cells has become a major obstacle for tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML). The BCR-ABL protein is an important client protein of heat shock protein 90 (Hsp90). BIIB021, an orally available Hsp90 inhibitor, has activity against various cancer cells. However, little is known about the inhibitory effect of BIIB021 on CML cells. We evaluated the inhibitory effects of BIIB021 on K562, K562/G (an imatinib-resistant cell lines), as well as 32D mouse leukemic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and T315I mutant BCR-ABL (32Dp210-T315I) cells. Our data showed that BIIB021 induced significant growth inhibition and apoptosis that was predominantly mediated by the mitochondrial pathway. BIIB021 also resulted in proteasomal degradation of BCR-ABL proteins. In addition to induction of apoptosis, we report for the first time that BIIB021 induced autophagic response as evidenced by the formation of autophagosome, increased conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, decreased p62 (SQSTM1) protein levels. Further study suggested that Akt-mTOR-Ulk1 signaling pathway was involved in BIIB021-triggered autophagy. Moreover, blocking autophagy using pharmacological inhibitor 3-methyladenine and bafilomycin A1 significantly enhanced cell death and apoptosis induced by BIIB021, indicating the cytoprotective role of autophagy in BIIB021-treated CML cells. Collectively, these data provide possible molecular mechanisms for the antileukemic effect of BIIB021 on imatinib-sensitive and -resistant CML cells and provide new insights into the future application of BIIB021 in the clinical treatment of CML.

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Specially, the mTOR/ULK1 signaling also generates autophagic protection in chronic myeloid leukemia cells, antagonizing the chemotherapeutic benefits of regular regimen [213]. However, contrary outcome has been obtained in breast cancer specimens, among which lower ULK1 expression indicates unfavorable prognosis and local development [214].…”

Synergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/Akt/mTOR and NF-κB signal pathways in thyroid carcinoma cells

“…Meanwhile, BIIB021 causes cell death by regulating mTOR-Ulk1 signal pathway in chronic myeloid leukemia cells [23]. In the present study, BIIB021 synergized with triptolide in induction of death of thyroid carcinoma cells, and thus the influence of BIIB021 in combination with triptolide on these signal pathways in thyroid carcinoma cells was investigated.…”

“…Meanwhile, BIIB021 results in death of chronic myeloid leukemia cells through regulation of mTOR-Ulk1 signal pathway [23]. In regard to involvement of mTOR in cell survival, it was reported that the dual mTOR inhibitor MLN0128 inhibited tumor growth in Merkel cell carcinoma-xenograft model [29].…”

Combined expression of miR-34a and Smac mediated by oncolytic vaccinia virus synergistically promote anti-tumor effects in Multiple Myeloma

“…After 48 hours, collecting cells and stained with prewarmed (37 °C) MitoTracker® probe (100–500 nM) for 15–45 minutes. Immunoflorescent staining for cytochrome c was performed as described previously46. In details, cells were washed with PBS, and then fixed with 4% paraformaldehyde.…”