Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line

Lu, Sangwei; Chen, Zhilong; Yang, Jianmin; Chen, Li; Gong, Shenglan; Zhou, Hong; Guo, Lieping; Wang, Jianmin

doi:10.1016/j.exphem.2008.04.013

Cited by 76 publications

(41 citation statements)

References 29 publications

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“…A different point mutation in the active center of the b5 polypeptide has been observed in T-cell lymphoma-type Jurkat cells, together with an increase in transcription of the respective gene. 22,23 Here, we directly compare the adaptive changes in three different cell lines generated under identical conditions, and observe an increased expression and also increased active species of the targeted as well as of the non-targeted active proteasome subunits. This argues that the resistance towards proteasome inhibitors is characterized by a mostly uniform reaction pattern consisting of the upregulation of proteasome transcription, expression and activity, which is triggered by proteasome inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23][24] Because of the different types of analysis, assay conditions, as well as differences in generating the individual bortezomib-adapted cell clones, it is difficult to assess to what extent bortezomib resistance follows a more general and qualitatively reproducible reaction pattern in different cells. Mutations in the active center of the b5 polypeptide have been repeatedly reported, which in part did, and in part did not lead to increased chymotryptic activity with and without overexpression of individual proteasome subunits.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the ubiquitin–proteasome system in bortezomib-adapted cells

et al. 2009

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Resistance towards the proteasome inhibitor bortezomib is poorly understood. We adapted the HL-60, ARH-77 and AMO-1 cell lines (myeloid leukemia, plasmocytoid lymphoma, myeloma) to bortezomib exceeding therapeutic plasma levels, and compared characteristics of the ubiquitin-proteasome system, alternative proteases and the unfolded protein response (UPR) between adapted cells and parental lines. Adapted cells showed increased transcription rates, activities and polypeptide levels of the bortezomib-sensitive b5, but also of the b2 proteasome subunit and consistently retained elevated levels of active b1/b5-type proteasome subunits in the presence of therapeutic levels of bortezomib. Bortezomib-adapted HL-60 cells showed increased expression and proteasome association of the 11S proteasome activator, and did not accumulate poly-ubiquitinated protein, activate the UPR or UPR-mediated apoptosis in response to bortezomib. The rate of protein biosynthesis was reduced, and the transcription of chaperone genes downmodulated. We did not observe major changes in the activities of TPPII, cathepsins or deubiquitinating proteases. We conclude that different types of bortezomib-adapted cell lines, including myeloma, show similar patterns of changes in the proteasomal machinery which result in residual proteasome activity in the presence of bortezomib and a quantitative balance between protein biosynthesis and destruction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of the ubiquitin–proteasome system in bortezomib-adapted cells

et al. 2009

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“…25,32,37 Up-regulated expression or mutations in PSMB5, which results in disrupted binding to bortezomib, have been implicated in drug resistance in lymphoid and myeloid malignancies. 25,32,37,38 Additional evidence that proteasome subunits play a role in bortezomib resistance comes from an RNAi screen to identify modulators of proteasome inhibitor sensitivity in MM. 51 According to this screen, the strongest bortezomib sensitizers were proteasome subunits (one of which was PSMA1).…”

Section: Traf6 and Bortezomib 865mentioning

confidence: 99%

“…25,[36][37][38] Therefore, down-regulation of PSMA1 in shTRAF6-expressing cells may reveal a mechanism resulting in increased sensitivity to bortezomib (despite a mutation in the PSMB5 subunit). To test this hypothesis, PSMA1 expression was depleted using 2 shRNAs in Bort-R cells and evaluated for sensitivity to bortezomib and proteasome function (Figure 6C-D).…”

Section: Traf6 Regulates the Expression Of Psma1mentioning

confidence: 99%

Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

Fang

Rhyasen

Bolanos

et al. 2012

Blood

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IntroductionMyelodysplastic syndrome (MDS) is a hematologic malignancy defined by blood cytopenias due to ineffective hematopoiesis, a predisposition to acute myeloid leukemia (AML), and genomic instability. 1,2 Molecular-targeted therapies do not exist for MDS and the mechanisms of current therapies are largely unknown. More recently, bortezomib (Velcade), which is widely used for the treatment of multiple myeloma (MM) and lymphomas, is being evaluated as a single agent or in combination with chemotherapy in certain MDS and AML patients. [3][4][5] Bortezomib is a selective and reversible inhibitor of the 26S proteasome, and mechanistic studies have revealed that inhibition of the proteasome complex leads to accumulation of lysine (K)-48 ubiquitin-linked proteins and consequently to cytotoxic effects in malignant cells. 6 Proapoptotic and cell-cycle inhibitor proteins are stabilized after proteasome inhibition and thought to contribute to the anticancer effect by inducing apoptosis and inhibiting the cell cycle, respectively. 6 Nevertheless, the molecular and cellular mechanisms of bortezomib-induced cytotoxicity remain unknown, particularly in MDS/AML. Whereas the role of bortezomib in regulating cell-cycle entry and survival have been characterized partially in MDS/AML, 7-9 recent evidence has pointed to a more general cellular effect: bortezomib treatment results in the accumulation of nondegraded proteins, leading to endoplasmic reticulum stress and autophagy in cancer. [10][11][12] Under normal cellular stresses, autophagy, a catabolic pathway, degrades long-lived proteins and defective and superfluous organelles. 13 However, under conditions of extreme cellular stress, autophagy is used by the cell to undergo death. 14 Human miR-146a, a candidate gene in del(5q) MDS/AML, is reduced significantly in del(5q) and normal karyotype MDS/AML patients. [15][16][17] TRAF6 is a key target of miR-146a 15,18,19 and, as expected, miR-146a-knockout mice have a dramatic increase in TRAF6 protein within the hematopoietic compartment. 20,21 Retroviral overexpression of TRAF6 in mouse hematopoietic stem/ progenitor cells results in MDS-like hematopoietic defects and progression to AML. 15 Bortezomib has been shown previously to be effective for an MDS patient with del(5q) and was also reported to reduce directly TRAF6 mRNA and protein in osteoclast precursors from MM patients. 22,23 Because TRAF6 is implicated in MDS/AML and bortezomib has been shown to be effective in del(5q) MDS and to inhibit TRAF6 in MM, we hypothesized that one mechanism of bortezomib action is through inhibition of TRAF6. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org FromIn the present study, we identified TRAF6 as a relevant target of bortezomib-induced...

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“…The three patients, excluding our patient, in whom bortezomib was effective against malignant pleural effusion complicating myeloma survived for a prolonged period, indicating that the prognosis of the disease may not necessarily be poor. It is hardly deniable that low-dose bortezomib therapy at 0.7 mg/m 2 induced resistance, resulting in the short-lived response of about 1 month in our patient (21)(22)(23)(24). Calculation of the optimal dose based on determination of the blood concentration of bortezomib is expected to be useful.…”

Section: Discussionmentioning

confidence: 99%

Response to Low-dose Bortezomib in Plasma Cell Leukemia Patients with Malignant Pleural Effusion and Ascites: A Case Report and a Review of the Literature

et al. 2012

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Pleural effusion or ascites complicating plasmacytoma is rare and has a poor prognosis. A 70-year-old man was diagnosed as plasma cell leukemia and one course of ranimustine-vindesine, melphalan, and prednisolone followed by melphalan and prednisone (MP) maintained a very good partial response. After MP he was diagnosed to have pleural effusion and ascites as a complication of the plasmacytoma. Low-dose bortezomib caused disappearance of the malignant effusion. The malignant effusions recurred after the end of the second course of bortezomib. High-dose dexamethasone vincristine, doxorubicin, cyclophosphamide, and prednisone yielded no benefit, the patient died of Aspergillus pneumonia.

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Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line

Cited by 76 publications

References 29 publications

Characterization of the ubiquitin–proteasome system in bortezomib-adapted cells

Characterization of the ubiquitin–proteasome system in bortezomib-adapted cells

Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

Response to Low-dose Bortezomib in Plasma Cell Leukemia Patients with Malignant Pleural Effusion and Ascites: A Case Report and a Review of the Literature

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