Low expression of pro-apoptotic proteins Bax, Bak and Smac indicates prolonged progression-free survival in chemotherapy-treated metastatic melanoma.


:Despite the introduction of novel targeted therapies, chemotherapy still remains the primary treatment for metastatic melanoma in poorly funded healthcare environments or in case of disease relapse, with no reliable molecular markers for progression-free survival (PFS) available. As chemotherapy primarily eliminates cancer cells by apoptosis, we here evaluated if the expression of key apoptosis regulators (Bax, Bak, Bcl-2, Bcl-xL, Smac, Procaspase-9, Apaf-1, Procaspase-3 and XIAP) allows prognosticating PFS in stage III/IV melanoma patients. Following antibody validation, marker expression was determined by automated and manual scoring of immunohistochemically stained tissue microarrays (TMAs) constructed from treatment-naive metastatic melanoma biopsies. Interestingly and counter-intuitively, low expression of the pro-apoptotic proteins Bax, Bak and Smac indicated better prognosis (log-rank p < 0.0001, p = 0.0301 and p = 0.0227 for automated and p = 0.0422, p = 0.0410 and p = 0.0073 for manual scoring). These findings were independently validated in the cancer genome atlas (TCGA) metastatic melanoma cohort (TCGA-SKCM) at transcript level (log-rank p = 0.0004, p = 0.0104 and p = 0.0377). Taking expression heterogeneity between the markers in individual tumour samples into account allowed defining combinatorial Bax, Bak, Smac signatures that were associated with significantly increased PFS (p = 0.0002 and p = 0.0028 at protein and transcript level, respectively). Furthermore, combined low expression of Bax, Bak and Smac allowed predicting prolonged PFS (> 12 months) on a case-by-case basis (area under the receiver operating characteristic curve (ROC AUC) = 0.79). Taken together, our results therefore suggest that Bax, Bak and Smac jointly define a signature with potential clinical utility in chemotherapy-treated metastatic melanoma.


Cell Death Dis


Cell death & disease


Guttà C,Rahman A,Aura C,Dynoodt P,Charles EM,Hirschenhahn E,Joseph J,Wouters J,de Chaumont C,Rafferty M,Warren M,van den Oord JJ,Gallagher WM,Rehm M




Has Abstract


2020-02-13 00:00:00












  • socs7, a target gene of microRNA-145, regulates interferon-β induction through STAT3 nuclear translocation in bladder cancer cells.

    abstract::We recently reported that microRNA (miR)-145 is downregulated and induces apoptosis in human bladder cancer cells. Also, it is suggested that the ectopic expression of miR-145 induces apoptosis with the induction of TRAIL expression in several cancer cells. Here, we demonstrated a novel mechanism of apoptosis inductio...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Noguchi S,Yamada N,Kumazaki M,Yasui Y,Iwasaki J,Naito S,Akao Y

    更新日期:2013-02-07 00:00:00

  • Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip.

    abstract::Studies on human intestinal injury induced by acute exposure to γ-radiation commonly rely on use of animal models because culture systems do not faithfully mimic human intestinal physiology. Here we used a human Gut-on-a-Chip (Gut Chip) microfluidic device lined by human intestinal epithelial cells and vascular endoth...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Jalili-Firoozinezhad S,Prantil-Baun R,Jiang A,Potla R,Mammoto T,Weaver JC,Ferrante TC,Kim HJ,Cabral JMS,Levy O,Ingber DE

    更新日期:2018-02-14 00:00:00

  • The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition.

    abstract::Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Hager S,Korbula K,Bielec B,Grusch M,Pirker C,Schosserer M,Liendl L,Lang M,Grillari J,Nowikovsky K,Pape VFS,Mohr T,Szakács G,Keppler BK,Berger W,Kowol CR,Heffeter P

    更新日期:2018-10-15 00:00:00

  • Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF.

    abstract::Induction of lethal autophagy has become a strategy to eliminate glioma cells, but it remains elusive whether autophagy contributes to cell death via causing mitochondria damage and nuclear translocation of apoptosis inducing factor (AIF). In this study, we find that silibinin induces AIF translocation from mitochondr...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wang C,He C,Lu S,Wang X,Wang L,Liang S,Wang X,Piao M,Cui J,Chi G,Ge P

    更新日期:2020-08-14 00:00:00

  • Modeling the function of BAX and BAK in early human brain development using iPSC-derived systems.

    abstract::Intrinsic apoptosis relies on the ability of the BCL-2 family to induce the formation of pores on the outer mitochondrial membrane. Previous studies have shown that both BAX and BAK are essential during murine embryogenesis, and reports in human cancer cell lines identified non-canonical roles for BAX and BAK in mitoc...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Joshi P,Bodnya C,Rasmussen ML,Romero-Morales AI,Bright A,Gama V

    更新日期:2020-09-25 00:00:00

  • PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis. Therefore, it is important to fully understand the molecular mechanism underlying its occurrence and development. Pumilio RNA-binding family member 1 (PUM1) has been reported to function as an oncogene in ovarian cancer and nonsmall...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Dai H,Shen K,Yang Y,Su X,Luo Y,Jiang Y,Shuai L,Zheng P,Chen Z,Bie P

    更新日期:2019-08-08 00:00:00

  • Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia.

    abstract::Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes. However, their functions in cerebral ischemia remain largely unknown. Through an lncRNA array analysis in a rat model of focal cerebral ischemia/reperfusion (I/R), we have identified CAMK2D-associ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Xu Q,Deng F,Xing Z,Wu Z,Cen B,Xu S,Zhao Z,Nepomuceno R,Bhuiyan MI,Sun D,Wang QJ,Ji A

    更新日期:2016-03-31 00:00:00

  • Non-viral FoxM1 gene delivery to hepatocytes enhances liver repopulation.

    abstract::Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocyte...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Xiang D,Liu CC,Wang MJ,Li JX,Chen F,Yao H,Yu B,Lu L,Borjigin U,Chen YX,Zhong L,Wangensteen KJ,He ZY,Wang X,Hu YP

    更新日期:2014-05-22 00:00:00

  • Preclinical studies using cisplatin/carboplatin to restore the Enzalutamide sensitivity via degrading the androgen receptor splicing variant 7 (ARv7) to further suppress Enzalutamide resistant prostate cancer.

    abstract::The FDA-approved anti-androgen Enzalutamide (Enz) has been used successfully as the last line therapy to extend castration-resistant prostate cancer (CRPC) patients' survival by an extra 4.8 months. However, CRPC patients eventually develop Enz-resistance that may involve the induction of the androgen receptor (AR) sp...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Chou FJ,Lin C,Tian H,Lin W,You B,Lu J,Sahasrabudhe D,Huang CP,Yang V,Yeh S,Niu Y,Chang C

    更新日期:2020-11-02 00:00:00

  • Age-severity matched cytokine profiling reveals specific signatures in Covid-19 patients.

    abstract::A global effort is currently undertaken to restrain the COVID-19 pandemic. Host immunity has come out as a determinant for COVID-19 clinical outcomes, and several studies investigated the immune profiling of SARS-CoV-2 infected people to properly direct the clinical management of the disease. Thus, lymphopenia, T-cell...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Angioni R,Sánchez-Rodríguez R,Munari F,Bertoldi N,Arcidiacono D,Cavinato S,Marturano D,Zaramella A,Realdon S,Cattelan A,Viola A,Molon B

    更新日期:2020-11-06 00:00:00

  • PIM kinases mediate resistance of glioblastoma cells to TRAIL by a p62/SQSTM1-dependent mechanism.

    abstract::Glioblastoma (GBM) is the most common and aggressive brain tumor and is associated with poor prognosis. GBM cells are frequently resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and finding new combinatorial therapies to sensitize glioma cells to TRAIL remains an important challenge. PIM ki...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Serrano-Saenz S,Palacios C,Delgado-Bellido D,López-Jiménez L,Garcia-Diaz A,Soto-Serrano Y,Casal JI,Bartolomé RA,Fernández-Luna JL,López-Rivas A,Oliver FJ

    更新日期:2019-01-18 00:00:00

  • A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy.

    abstract::Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wu QY,Cheng Z,Zhou YZ,Zhao Y,Li JM,Zhou XM,Peng HL,Zhang GS,Liao XB,Fu XM

    更新日期:2020-02-18 00:00:00

  • CD45+CD33lowCD11bdim myeloid-derived suppressor cells suppress CD8+ T cell activity via the IL-6/IL-8-arginase I axis in human gastric cancer.

    abstract::Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro-tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45+CD33lowCD11bdim MDSCs in the periphe...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Mao FY,Zhao YL,Lv YP,Teng YS,Kong H,Liu YG,Wu XL,Hao CJ,Chen W,Duan MB,Han B,Ma Q,Wang TT,Peng LS,Zhang JY,Cheng P,Su CY,Fu XL,Zou QM,Guo G,Guo XL,Zhuang Y

    更新日期:2018-07-09 00:00:00

  • CCT3 acts upstream of YAP and TFCP2 as a potential target and tumour biomarker in liver cancer.

    abstract::Although Yes-associated protein (YAP) is very important to liver cancer, its nuclear localisation prevents consideration as a promising therapeutic target and a diagnostic biomarker. Recently, we reported that the protumourigenic roles of YAP in liver cancer are indispensable for transcription factor CP2 (TFCP2) in a ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Liu Y,Zhang X,Lin J,Chen Y,Qiao Y,Guo S,Yang Y,Zhu G,Pan Q,Wang J,Sun F

    更新日期:2019-09-09 00:00:00

  • Kinesin-14 motor protein KIFC1 participates in DNA synthesis and chromatin maintenance.

    abstract::The nuclear localization signal (NLS) in kinesin-14 KIFC1 is associated with nuclear importins and Ran gradient, but detailed mechanism remains unknown. In this study, we found that KIFC1 proteins have specific transport characteristics during cell cycle. In the absence of KIFC1, cell cycle kinetics decrease significa...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wei YL,Yang WX

    更新日期:2019-05-24 00:00:00

  • miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury.

    abstract::Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we inv...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Ding C,Ding X,Zheng J,Wang B,Li Y,Xiang H,Dou M,Qiao Y,Tian P,Xue W

    更新日期:2020-10-28 00:00:00

  • The bHLH transcription factor DEC1 promotes thyroid cancer aggressiveness by the interplay with NOTCH1.

    abstract::Aberrant re-activation of transcription factors occurs frequently in cancer. Recently, we found the basic helix-loop-helix transcription factors DEC1 and DEC2 significantly up-regulated in a model of highly aggressive thyroid cancer, raising the hypothesis that these factors might be part of the program driving progre...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Gallo C,Fragliasso V,Donati B,Torricelli F,Tameni A,Piana S,Ciarrocchi A

    更新日期:2018-08-29 00:00:00

  • Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma.

    abstract::It is largely recognized that fibroblast activation protein (FAP) is expressed in cancer-associated fibroblasts (CAFs) of many human carcinomas. Furthermore, FAP was recently also reported to be expressed in carcinoma cells of the breast, stomach, pancreatic ductal adenocarcinoma, colorectum, and uterine cervix. The c...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wang H,Wu Q,Liu Z,Luo X,Fan Y,Liu Y,Zhang Y,Hua S,Fu Q,Zhao M,Chen Y,Fang W,Lv X

    更新日期:2014-04-10 00:00:00

  • The pharmalogical reactivation of p53 function improves breast tumor cell lysis by granzyme B and NK cells through induction of autophagy.

    abstract::Cytotoxic T lymphocytes (CTL) and natural killer cells (NK)-mediated elimination of tumor cells is mostly dependent on Granzyme B apoptotic pathway, which is regulated by the wild type (wt) p53 protein. Because TP53 inactivating mutations, frequently found in human tumors, could interfere with Granzyme B-mediated cell...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Chollat-Namy M,Ben Safta-Saadoun T,Haferssas D,Meurice G,Chouaib S,Thiery J

    更新日期:2019-09-20 00:00:00

  • Human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy.

    abstract::In most clinical trials, human mesenchymal stem cells (hMSCs) are expanded in vitro before implantation. The genetic stability of human stem cells is critical for their clinical use. However, the relationship between stem-cell expansion and genetic stability is poorly understood. Here, we demonstrate that within the n...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Estrada JC,Torres Y,Benguría A,Dopazo A,Roche E,Carrera-Quintanar L,Pérez RA,Enríquez JA,Torres R,Ramírez JC,Samper E,Bernad A

    更新日期:2013-06-27 00:00:00

  • Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension.

    abstract::Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertens...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Zhang ML,Zhao GL,Hou Y,Zhong SM,Xu LJ,Li F,Niu WR,Yuan F,Yang XL,Wang Z,Miao Y

    更新日期:2020-09-10 00:00:00

  • Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation.

    abstract::The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumorigenesis. Accumulati...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Li C,Chang DL,Yang Z,Qi J,Liu R,He H,Li D,Xiao ZX

    更新日期:2013-12-05 00:00:00

  • Adoptive transfer of Th1-conditioned lymphocytes promotes axonal remodeling and functional recovery after spinal cord injury.

    abstract::The role of T lymphocytes in central nervous system (CNS) injuries is controversial, with inconsistent results reported concerning the effects of T-lymphocyte transfer on spinal cord injury (SCI). Here, we demonstrate that a specific T-lymphocyte subset enhances functional recovery after contusion SCI in mice. Intrape...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Ishii H,Jin X,Ueno M,Tanabe S,Kubo T,Serada S,Naka T,Yamashita T

    更新日期:2012-08-09 00:00:00

  • A split-GFP tool reveals differences in the sub-mitochondrial distribution of wt and mutant alpha-synuclein.

    abstract::Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuronal loss that initiates in the substantia nigra pars compacta and by the formation of intracellular inclusions mainly constituted by aberrant α-synuclein (α-syn) deposits known as Lewy bodies. Most cases ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Vicario M,Cieri D,Vallese F,Catoni C,Barazzuol L,Berto P,Grinzato A,Barbieri L,Brini M,Calì T

    更新日期:2019-11-12 00:00:00

  • Heme oxygenase-1 protects against Alzheimer's amyloid-β(1-42)-induced toxicity via carbon monoxide production.

    abstract::Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer's disease, catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediates cellular K+ efflux as an early step in the apoptotic cascade. Sin...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Hettiarachchi N,Dallas M,Al-Owais M,Griffiths H,Hooper N,Scragg J,Boyle J,Peers C

    更新日期:2014-12-11 00:00:00

  • Hsp90 modulates the stability of MLKL and is required for TNF-induced necroptosis.

    abstract::The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a key component of tumor necrosis factor (TNF)-induced necroptosis and plays a crucial role in necroptosis execution. However, the mechanisms that control MLKL activity are not completely understood. Here, we identify the molecular chaperone Hsp90 as ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Zhao XM,Chen Z,Zhao JB,Zhang PP,Pu YF,Jiang SH,Hou JJ,Cui YM,Jia XL,Zhang SQ

    更新日期:2016-02-11 00:00:00

  • The transient expression of miR-203 and its inhibiting effects on skeletal muscle cell proliferation and differentiation.

    abstract::Previous studies have shown that miR-203 is a skin-specific microRNA (miRNA) with a profound role in skin cell differentiation. However, emerging microarray and deep sequencing data revealed that miR-203 is also expressed in embryonic skeletal muscle and myoblasts. In this study, we found that miR-203 was transiently ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Luo W,Wu H,Ye Y,Li Z,Hao S,Kong L,Zheng X,Lin S,Nie Q,Zhang X

    更新日期:2014-07-17 00:00:00

  • Akt inhibitor SC66 promotes cell sensitivity to cisplatin in chemoresistant ovarian cancer cells through inhibition of COL11A1 expression.

    abstract::We studied Akt inhibition using SC66 in a NOD-SCID xenograft mouse model and a panel of eight ovarian cancer cell lines. Elevated phospho-Akt levels in cancerous tissue were associated with short progression-free survival and overall survival. Cell sensitivity to SC66 was inversely correlated with phospho-Akt and COL1...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Wu YH,Huang YF,Chen CC,Chou CY

    更新日期:2019-04-11 00:00:00

  • CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.

    abstract::The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Scudiero I,Mazzone P,D'Andrea LE,Ferravante A,Zotti T,Telesio G,De Rubis G,Reale C,Pizzulo M,Muralitharan S,Vito P,Stilo R

    更新日期:2017-02-23 00:00:00

  • Inhibition of AIM2 inflammasome activation alleviates GSDMD-induced pyroptosis in early brain injury after subarachnoid haemorrhage.

    abstract::Only a few types of inflammasomes have been described in central nervous system cells. Among these, the absent in melanoma 2 (AIM2) inflammasome is primarily found in neurons, is highly specific and can be activated only by double-stranded DNA. Although it has been demonstrated that the AIM2 inflammasome is activated ...

    journal_title:Cell death & disease

    pub_type: 杂志文章


    authors: Yuan B,Zhou XM,You ZQ,Xu WD,Fan JM,Chen SJ,Han YL,Wu Q,Zhang X

    更新日期:2020-01-30 00:00:00