Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik

Lopez, Jonathan; Hesling, Cédric; Prudent, Julien; Popgeorgiev, Nikolay; Gadet, Rudy; Mikaélian, Ivan; Rimokh, Ruth; Gillet, Germain; Gonzalo, Philippe

doi:10.1038/cdd.2012.21

Cited by 47 publications

(52 citation statements)

References 38 publications

(41 reference statements)

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“…In contrast, dysfunction of later stages of autophagy (e.g., by CQ [47] or Lamp2 shRNA [13]) led to marked Bik accumulation and apoptosis induced by GX plus FP. Furthermore, these findings suggest that Bik accumulation stems from cargo loading failure secondary to p62 downregulation (e.g., by Cdk9 inhibition or p62 shRNA), evidenced by a reduction in the amount of Bik harbored by SDS-insoluble protein aggregates and the marked accumulation of ubiquitinated Bik (51). Finally, the dual roles of Bik are highlighted by the observations that knockdown of Bik by shRNA substantially reduced autophagy induced by GX and prevented apoptosis triggered by cotreatment with GX and FP both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 94%

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Chen

Zhou

Zhang

et al. 2014

Molecular and Cellular Biology

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eIn selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a timedependent manner during autophagy, inhibition or knockdown of Cdk9/cyclin T1 transcriptionally downregulated SQSTM1/ p62 but did not affect autophagic flux. These interventions, or short hairpin RNA (shRNA) directly targeting SQSTM1/p62, resulted in cargo loading failure and inefficient autophagy, phenomena recently described for Huntington's disease neurons. These events led to the accumulation of the BH3-only protein NBK/Bik on endoplasmic reticulum (ER) membranes, most likely by blocking loading and autophagic degradation of NBK/Bik, culminating in apoptosis. Whereas NBK/Bik upregulation was further enhanced by disruption of distal autophagic events (e.g., autophagosome maturation) by chloroquine (CQ) or Lamp2 shRNA, it was substantially diminished by inhibition of autophagy initiation (e.g., genetically by shRNA targeting Ulk1, beclin-1, or Atg5 or pharmacologically by 3-methyladenine [3-MA] or spautin-1), arguing that NBK/Bik accumulation stems from inefficient autophagy. Finally, NBK/Bik knockdown markedly attenuated apoptosis in vitro and in vivo. Together, these findings identify novel cross talk between autophagy and apoptosis, wherein targeting SQSTM1/p62 converts cytoprotective autophagy to an inefficient form due to cargo loading failure, leading to NBK/Bik accumulation, which triggers apoptosis.A utophagy is an evolutionarily conserved process by which damaged organelles and unneeded proteins are degraded by lysosomes to maintain intracellular homeostasis and to recycle cellular nutrients. While autophagy can promote cell death (1), in most cases, it is cytoprotective and contributes to drug resistance (2). In response to chemotherapeutic agents, apoptosis (type I) and autophagy (type II) represent two major forms of programmed cell death (3). Autophagy and apoptosis share molecular regulatory mechanisms governed by Bcl-2 family proteins (3, 4). Specifically, Bcl-2 and Bcl-x L prevent both apoptosis and autophagy by sequestering different BH3-only proteins (e.g., proapoptotic Bim and Bid [5] and proautophagic beclin-1 [6,7]). As a result, antagonism of Bcl-2/Bcl-x L function releases and activates these BH3-only proteins, leading to apoptosis and autophagy, respectively (8). While apoptosis represents a well-established mechanism of action of conventional and targeted anticancer agents (3), autophagy may play both positive and negative roles in tumorigenesis and cancer treatment (9, 10). Consequently, whether autophagy should be inhibited or activated remains the subject of debate. Accordingly, both autophagy inhibitors and inducers are currently undergoing clinical evaluation (11).Protection of cells from injury by harmful macromolecules or damaged organelles through autophagy as a quality control (QC) mechanism (11, 12) involves the sequestration and tran...

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Section: Discussionmentioning

confidence: 94%

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Chen

Zhou

Zhang

et al. 2014

Molecular and Cellular Biology

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“…This effect relies on the activation of the Ras-Raf-Mek1/2-Erk1/2 pathway and on the phosphorylation of Bik on Thr124, driving Bik ubiquitylation on Lys33 and subsequent degradation by the proteasome. These results suggest that Bik could be a rate-limiting factor for apoptosis induction of tumor cells exhibiting deregulated Erk1/2 signaling, which may provide new opportunities for cancer therapies (129).…”

Section: Bcl-2 Family Of Proteins and Their Effect In Resistance To Tmentioning

confidence: 91%

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

et al. 2014

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Abstract. Anti-estrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor-positive breast tumors. Patients with estrogen receptor-positive breast cancer initially respond to treatment with anti-hormonal agents such as tamoxifen, but remissions are often followed by the acquisition of resistance and, ultimately, disease relapse. The development of a rationale for the effective treatment of tamoxifen-resistant breast cancer requires an understanding of the complex signal transduction mechanisms. In the present study, we explored some mechanisms associated with resistance to tamoxifen, such as pharmacologic mechanisms, loss or modification in estrogen receptor expression, alterations in co-regulatory proteins and the regulation of the different signaling pathways that participate in different cellular processes such as survival, proliferation, stress, cell cycle, inhibition of apoptosis regulated by the Bcl-2 family, autophagy, altered expression of microRNA, and signaling pathways that regulate the epithelial-mesenchymal transition in the tumor microenvironment. Delineation of the molecular mechanisms underlying the development of resistance may aid in the development of treatment strategies to enhance response and compromise resistance.

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“…Recently, ERK1/2 was proposed to regulate the stability of the BH3-only protein BIK, in a manner analogous to BIM (Lopez et al, 2012). Direct phosphorylation of BIK on Thr124 by ERK1/2 was suggested to promote ubiquitination and subsequent proteasome-mediated degradation of BIK.…”

Section: Figurementioning

confidence: 99%

That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance

Sale

Cook

2013

British J Pharmacology

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Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6-9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumour cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here we discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic. LINKED ARTICLESThis article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2013.169.issue-8 Abbreviations A1, BCL2-related protein A1; AP1, activator protein 1; APAF1, apoptotic peptidase activating factor 1; ARAF, v-raf murine sarcoma 3611 viral oncogene homologue; BAD, BCL-XL/BCL2-associated death promoter; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated x protein; BCL2, B-cell lymphoma 2; BCL-XL, B-cell lymphoma extra large; BH3, BCL2 homology domain 3; BID, BH3 interacting domain death agonist; BIK, BCL2-interacting killer; BIM, BCL2-interacting mediator of cell death; BMF, BCL2-modifying factor; BRAF, v-raf murine sarcoma viral oncogene homologue B1; CCND1, cyclin D1; CDC25A, cell division cycle 25 homologue A; CDK, cyclin-dependent kinase; CIP1, CDK-interacting protein 1; CRAF, v-raf-1 murine leukaemia viral oncogene homologue 1; CREB, cAMP responsive element binding protein; DKO, double knockout; EGFR, epidermal growth factor receptor; CRC, colorectal cancer; ELK1, ETS-like gene 1; EMT, epithelial-mesenchymal transition; ETS, v-ets erythroblastosis virus E26 oncogene homologue; FOXO3, forkhead box O 3; G1, growth phase 1; GSK3, glycogen synthase kinase 3; HIV, human immunodeficiency virus; HRAS, v-Ha-ras Harvey rat sarcoma viral oncogene homologue...

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Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik

Cited by 47 publications

References 38 publications

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance

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