Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1

Maddalena, Francesca; Sisinni, Lorenza; Lettini, Giacomo; Condelli, Valentina; Matassa, Danilo Swann; Piscazzi, Annamaria; Amoroso, Maria Rosaria; Torre, Giuseppe La; Esposito, Franca; Landriscina, Matteo

doi:10.1016/j.molonc.2013.04.009

Cited by 69 publications

(88 citation statements)

References 40 publications

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“…Adaptation to ER stress conditions represents a mechanism of resistance to taxanes [8][9][10]; interestingly, our data show that paclitaxel induces apoptotic cell death and caspase 12 activation in MCF7 BC cells and enhances BiP/Grp78 and Grp94 expression [7]. Also in this context, a role of TRAP1 has been demonstrated by our groups: in fact, paclitaxel induces TRAP1 protein levels in MCF7 and MDA-MB231 BC cells, without affecting its mRNA expression.…”

supporting

confidence: 73%

“…Using several inducible Myc cell models, as well as genetic and pharmacologic tools, Hart et al [26] have recently shown that Myc induction leads to activation of the PERK/eIF2α/ATF4 axis of the UPR, resulting in increased autophagy and protection against ER stress-dependent apoptosis. Similarly, we have demonstrated in CRC that increased TRAP1 expression correlates with increased expression of Myc, Grp78/BiP, ATF4 and increased phosphorylation of eIF2α [7,13,25].…”

Section: Trap1 Regulation Of Tumour Cell Metabolism Is Based On Attensupporting

confidence: 61%

“…We observed significant cytoprotective activity toward these agents due to re-expression of both wild type TRAP1 and the mitochondrial import-defective TRAP1 mutant, confirming the relevant role of TRAP1 in the protection from ER stress and in protein quality control, and that this function, exerted from ER-associated TRAP1, is relevant for its antiapoptotic activity. Consistently, the combination of paclitaxel with sub-cytotoxic concentrations of Gamitrinib, that targets the mitochondria-resident TRAP1 only, resulted in additive apoptotic effects in BC MCF7 cells as well as only partially reverting resistance to this agent in paclitaxel-resistant MCF7 cells [7].…”

mentioning

confidence: 66%

“…Among 23 BCs characterized for both TRAP1 and BiP/Grp78 expression, a significant co-upregulation of the two genes was observed [7]. These data suggest that UPR is activated in a significant subgroup of human BCs, as a result of chronic exposure to ER stress conditions, and that, remarkably, TRAP1 is part of this cell response to ER stress.…”

mentioning

confidence: 75%

“…Moreover, ER-associated TRAP1 modulates the activation of stress pathways responsible for regulation of protein synthesis rate and survival responses: PERK and eIF2α are in fact efficiently phosphorylated in control MCF7 cells upon paclitaxel exposure, whereas downregulation of TRAP1 resulted in reduced activation of the PERK/eIF2α pathway. Interestingly, in addition to being insensitive to paclitaxel, paclitaxel-resistant cells exhibited resistance to other agents inducing ER stress (i.e., thapsigargin and bortezomib), whereas TRAP1 down-regulation by siRNA re-established sensitivity to both paclitaxel and ER stress inducers [7]. These data suggest that adaptation to paclitaxel and ER stress share common molecular mechanisms and that TRAP1 plays a role in taxane resistance through ER stress protection.…”

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confidence: 90%

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ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

Matassa

Arzeni

Landriscina

et al. 2014

Endoplasmic Reticulum Stress in Diseases

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Abbreviations TRAPis involved in ER stress protection of cancer cellsTRAP1 (Tumour Necrosis Factor Receptor-Associated Protein 1) is a molecular chaperone, member of the HSP90 family, that contributes to the overall survival of cancer cells and is up-regulated in most tumour types (reviewed in 1). A large body of literature demonstrates that TRAP1 is part of a pro-survival signalling pathway aimed at evading the toxic effects of oxidants and anticancer drugs and plays a role in protecting mitochondria against apoptotic stimuli (reviewed in 2). However, whether its roles are uniformly oncogenic or not is now a matter of intense debate. Interestingly, Yoshida and colleagues [3] propose a more subtle reading of TRAP1 roles in the regulation of cellular metabolism and its impact on tumorigenesis. In fact, an inverse correlation between TRAP1 expression and tumor stage in cervical, bladder, and clear cell renal cell carcinoma was demonstrated. These conflicting observations on TRAP1 "behaviour" in different biological contexts is strictly related to a specific molecular complex/integrated network in which TRAP1 represents one of the focal nodes.Abstract: TRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles' homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.

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confidence: 73%

Section: Trap1 Regulation Of Tumour Cell Metabolism Is Based On Attensupporting

confidence: 61%

mentioning

confidence: 66%

mentioning

confidence: 75%

mentioning

confidence: 90%

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ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

Matassa

Arzeni

Landriscina

et al. 2014

Endoplasmic Reticulum Stress in Diseases

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Combination of dihydromyricetin and ondansetron strengthens antiproliferative efficiency of adriamycin in K562/ADR through downregulation of SORCIN: A new strategy of inhibiting P‐glycoprotein

Sun

Liu

Wang

et al. 2018

Journal Cellular Physiology

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Though the advancement of chemotherapy drugs alleviates the progress of cancer, long-term therapy with anticancer agents gradually leads to acquired multidrug resistance (MDR), which limits the survival outcomes in patients. It was shown that dihydromyricetin (DMY) could partly reverse MDR by suppressing P-glycoprotein (P-gp) and soluble resistance-related calcium-binding protein (SORCIN) independently. To reverse MDR more effectively, a new strategy was raised, that is, circumventing MDR by the coadministration of DMY and ondansetron (OND), a common antiemetic drug, during cancer chemotherapy. Meanwhile, the interior relation between P-gp and SORCIN was also revealed. The combination of DMY and OND strongly enhanced antiproliferative efficiency of adriamycin (ADR) because of the increasing accumulation of ADR in K562/ADR-resistant cell line. DMY could downregulate the expression of SORCIN and P-gp via the ERK/Akt pathways, whereas OND could not. In addition, it was proved that SORCIN suppressed ERK and Akt to inhibit P-gp by the silence of SORCIN, however, not vice versa. Finally, the combination of DMY, OND, and ADR led to G2/M cell cycle arrest and apoptosis via resuming P53 function and restraining relevant proteins expression. These fundamental findings provided a promising approach for further treatment of MDR.

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TRAP1 controls cell cycle G2–M transition through the regulation of CDK1 and MAD2 expression/ubiquitination

Sisinni

Maddalena

Condelli

et al. 2017

The Journal of Pathology

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Regulation of tumour cell proliferation by molecular chaperones is still a complex issue. Here, the role of the HSP90 molecular chaperone TRAP1 in cell cycle regulation was investigated in a wide range of human breast, colorectal, and lung carcinoma cell lines, and tumour specimens. TRAP1 modulates the expression and/or the ubiquitination of key cell cycle regulators through a dual mechanism: (i) transcriptional regulation of CDK1, CYCLIN B1, and MAD2, as suggested by gene expression profiling of TRAP1-silenced breast carcinoma cells; and (ii) post-transcriptional quality control of CDK1 and MAD2, being the ubiquitination of these two proteins enhanced upon TRAP1 down-regulation. Mechanistically, TRAP1 quality control on CDK1 is crucial for its regulation of mitotic entry, since TRAP1 interacts with CDK1 and prevents CDK1 ubiquitination in cooperation with the proteasome regulatory particle TBP7, this representing the limiting factor in TRAP1 regulation of the G2-M transition. Indeed, TRAP1 silencing results in enhanced CDK1 ubiquitination, lack of nuclear translocation of CDK1/cyclin B1 complex, and increased MAD2 degradation, whereas CDK1 forced up-regulation partially rescues low cyclin B1 and MAD2 levels and G2-M transit in a TRAP1-poor background. Consistently, the CDK1 inhibitor RO-3306 is less active in a TRAP1-high background. Finally, a significant correlation was observed between TRAP1 and Ki67, CDK1 and/or MAD2 expression in breast, colorectal, and lung human tumour specimens. This study represents the first evidence that TRAP1 is relevant in the control of the complex machinery that governs cell cycle progression and mitotic entry and provides a strong rationale to regard TRAP1 as a biomarker to select tumours with deregulated cell cycle progression and thus likely poorly responsive to novel cell cycle inhibitors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1

Cited by 69 publications

References 40 publications

ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

Combination of dihydromyricetin and ondansetron strengthens antiproliferative efficiency of adriamycin in K562/ADR through downregulation of SORCIN: A new strategy of inhibiting P‐glycoprotein

TRAP1 controls cell cycle G2–M transition through the regulation of CDK1 and MAD2 expression/ubiquitination

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