Cell Death & Disease

SOCS1 and SOCS3 genes, frequently repressed in hepatocellular carcinoma (HCC), function as tumor suppressors in hepatocytes. However, TCGA transcriptomic data revealed that SOCS1-low/SOCS3-high specimens displayed more aggressive HCC than SOCS1-low/SOCS3-low cases. We show that hepatocyte-specific Socs1-deficient livers upregulate Socs3 expression following genotoxic stress. Whereas deletion of Socs1 or Socs3 increased HCC susceptibility, ablation of both genes attenuated HCC growth. SOCS3 promotes p53 activation in SOCS1-deficient livers, leading to increased expression of CDKN1A (p21WAF1/CIP1), which coincides with elevated expression and transcriptional activity of NRF2. Deleting Cdkn1a in SOCS1-deficient livers diminished NRF2 activation, oxidative stress and HCC progression. Elevated CDKN1A expression and enrichment of antioxidant response genes also characterized SOCS1-low/SOCS3-high HCC. SOCS1 expression in HCC cell lines reduced oxidative stress, p21 expression and NRF2 activation. Our findings demonstrate that SOCS1 controls the oncogenic potential of SOCS3-driven p53-p21-NRF2 axis and suggest that NRF2-mediated antioxidant response represents a drug target in SOCS1-deficient HCC.

In a published Correction1, a revised analysis updated two "core transcription programs" proposed to underlie axon injury-induced retinal ganglion cell (RGC) neurodegeneration. Though extensive, the Correction purported to leave the two principal conclusions of its parent study2 unaltered. The first of those findings was that a core program mediated by the Activating Transcription Factor-4 (ATF4) and its likely heterodimeric partner does not include numerous canonical ATF4 target genes stimulated by RGC axon injury. The second was that the Activating Transcription Factor-3 (ATF3) and C/EBP Homologous Protein (CHOP) function with unprecedented coordination in a parallel program regulating innate immunity pathways. Here those unexpected findings are revealed to instead reflect insufficient knockout coupled with differences in RGC enrichment across conditions. This analysis expands on the published Corrections redefinition of the purported transcription programs to raise foundational questions about the proposed functions and relationships of these transcription factors in neurodegeneration.

Apoptosis plays a role in cell homeostasis in both normal development and disease. Bcl-xL, a member of the Bcl-2 family of proteins, regulates the intrinsic mitochondrial pathway of apoptosis. It is overexpressed in several cancers. Bcl-xL has a dual subcellular localization and is found at the mitochondria as well as the endoplasmic reticulum (ER). However, the biological significance of its ER localization is unclear. In order to decipher the functional contributions of the mitochondrial and reticular pools of Bcl-xL, we generated genetically modified mice expressing exclusively Bcl-xL at the ER, referred to as ER-xL, or the mitochondria, referred to as Mt-xL. By performing cell death assays, we showed that ER-xL MEFs show increased vulnerability to apoptotic stimuli but are more resistant to ER stress. Furthermore, ER-xL MEFs demonstrated a reduced expression of the Unfolded Protein Response (UPR) markers upon ER stress and displayed reduced inositol trisphosphate receptor (IP3R)-mediated ER calcium release. Collectively, our data show that upon ER stress, Bcl-xL negatively regulates IP3R-mediated calcium flux from the ER, which prevents ER calcium depletion and maintains the UPR and subsequent cell death in check. This work reveals a moonlighting function of Bcl-xL at the ER, apart from its cliche regulation of apoptosis.

Reactive oxygen species (ROS) function as potent activators of chaperone-mediated autophagy (CMA). While previous investigations have demonstrated that CMA facilitates cancer cell survival through selective degradation of oxidatively damaged proteins, the precise molecular mechanisms remain poorly defined. Hence, it is important to investigate the correlation between CMA and the antioxidative stress within tumor cells and elucidate its specific mechanism. LAMP2A expression profiles in gastric carcinoma cell lines and clinical specimens were quantified via qPCR, WB and immunohistochemical analysis. An in vitro oxidative stress model was established through 24-hour hydrogen peroxide (H2O2) exposure. Gastric cancer cell models with knockdown and overexpression of LAMP2A were established. Apoptotic indices and proliferative capacity were assessed through high-throughput flow cytometry and CCK-8 viability assays. The interaction between LAMP2A and DJ-1 was investigated via co-immunoprecipitation and confocal microscopy. This study demonstrates that LAMP2A is upregulated in gastric cancer and further induced by oxidative stress. Down-regulated LAMP2A impaired CMA functionality, sensitizing gastric cancer cells to oxidative cytotoxicity and significantly augmenting apoptosis rates. Elevated DJ-1 levels in gastric cancer cells are further amplified by oxidative stress, with severe stress enhancing LAMP2A-DJ-1 colocalization. Mechanistically, CMA inhibition precipitated accumulation of hyperoxidized DJ-1 isoforms, concomitant with pro-apoptotic BAX upregulation and anti-apoptotic BCL-2 downregulation. We found hyperoxidized DJ-1 as a novel CMA substrate. The LAMP2A-DJ-1 regulatory axis represents a critical adaptive mechanism whereby CMA activation maintains redox homeostasis in gastric malignancies. Specifically, CMA-mediated clearance of oxidized DJ-1 prevents pro-apoptotic protein cascade activation, thereby conferring oxidative stress resistance and promoting tumor cell survival.

Understanding how the malignant cells respond to chemotherapy is essential to prevent the development of resistance and to improve the efficiency of anti-cancer drugs. Recently, we established that, by intrinsic and paracrine mechanisms, taxol treatment in breast tumor cells increases NOXA a pro-apoptotic protein functioning as an endogenous inhibitor of survival protein MCL-1, thereby enhancing cytotoxic load on the compensatory survival protein BCL-xL. We herein sought to define the contribution of NOXA/MCL-1 to the modality of cell death secretome composition upon anti-mitotic treatment associated with a BCL-xL antagonist. We observed that genetic inactivation of NOXA (enforcing MCL-1 pro-survival activity) in cancer cells not only delays their death when exposed to taxol in combination with the BCL-xL antagonist A1331852, but also alters its morphological characteristics with the apparition of features evoking pyroptosis. We identified the Caspase3-GSDME axis as regulating pyroptotic-like features suggesting that NOXA may act as a negative regulator of this cell death process (and MCL-1 as a positive regulator for it). Furthermore, comparative analysis of secretomes from the NOXA proficient or deficient cancer cells treated by taxol reveals variations in inflammatory cytokine production including those of IL-1{beta} and IL-18. Thus, our results show that anti-mitotic treatments are able to induce death by apoptosis and/or pyroptosis depending on BCL-2 family balance in breast cancer cells. Furthermore, NOXA/MCL-1 ratio appears to control the communication between these two types of cell death and their associated extracellular inflammatory signals in coordination with the pore-forming gasdermin GSDME.

Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL-based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 activation in response to TNF, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies and Natural Killer cells.

Apoptotic neuron death is a key feature of neurodegenerative disease. Considerable efforts have been made to target this pathway but the molecular mechanisms remain incompletely understood. Here, we conducted an unbiased whole genome CRISPR inhibition screen in human neurons to discover genes required for their death and identified known targets including the kinase MAP3K12 (DLK) and the transcription factor JUN. In addition, this screen revealed a potential role for the transcription factor ATF2. We demonstrate that ATF2 phosphorylation by MAP3 kinases is the core driver of the pro-apoptotic transcriptional response. Surprisingly, JUN phosphorylation is not required for apoptosis. However, the phosphorylation of ATF2 and upregulation of JUN expression are crucial. ATF2 therefore converts the kinase signal into a transcriptional response. Inhibiting ATF2 in cultured human neurons prevents cell death. Notably we show that ATF2 knockdown is neuroprotective in injury models in vivo. Thus, ATF2 provides a promising new target for a wide range of neurodegenerative disorders.

HER2 is considered as a driver oncogene responsible for the HER2+ subtype of breast cancer. However, it is still unclear how HER2 induces the oncogenic transformation of breast cancer stem cells (BCSCs) and initiates tumorigenesis during premalignant stage breast cancer. Here, we used clinical samples and mouse models of HER2+ breast cancer to demonstrate that neither BCSCs nor their cell-of-origin express HER2/Neu in early-stage breast tumors. Instead, our results demonstrate that Neu overexpression results in the transformation of BCSCs in a non-cell-autonomous manner via triggering DNA damage and somatic mutagenesis in their Neu-negative cell-of-origin. This is caused by the increased oxidative stress in the tissue microenvironment generated by altered energy metabolism and increased reactive oxygen species levels in Neu-overexpressing mammary ducts. Therefore, our findings illustrate a previously unrecognized mechanism of HER2-induced breast tumor initiation in vivo with potential impacts on future preventive treatments for HER2+ premalignant breast cancer.

Patients with traumatic brain injury (TBI) frequently exhibit heightened pain and associated complications such as cognitive decline, depression, and anxiety. GPR37 is widely expressed in various brain regions, but its function remains largely unclear. We recently discovered neuroprotectin D1 (NPD1) as a novel GPR37 ligand. In this study, we examined the protective role of the NPD1/GPR37 signaling pathway in TBI-induced neuropathic pain and its complications. TBI was induced by closed-head impact and resulted in transient neuropathic pain for less than two weeks, showing periorbital and cutaneous mechanical allodynia/hyperalgesia, as well as motor deficiency and cognitive impairment. We found that peri-surgical treatment with NPD1, effectively prevented TBI-induced mechanical hypersensitivity, motor deficiency, and cognitive impairment. NPD1 treatment also substantially inhibited TBI-induced microgliosis, astrogliosis (including A1 astrocyte markers), and neuroinflammation in the sensory cortex and hippocampus. RNA sequencing and GO enrichment analysis revealed downregulations of genes related to "calcium ion homeostasis," and "GPCR signaling pathway" in the TBI-affected brain. These downregulations were restored by NPD1 treatment. RNAscope in situ hybridization revealed predominant Gpr37 mRNA expression in oligodendrocytes. TBI resulted in rapid and remarkable demyelination and downregulation of Gpr37 mRNA expression in oligodendrocytes, and both were protected by NPD1 treatment. NPD1s inhibition of periorbital and cutaneous mechanical pain was abolished in Gpr37-/- mice. Moreover, TBI-induced neuropathic pain was prolonged by swimming stress, and NPD1 treatment prevented the stress-induced transition from acute to chronic pain in wild-type mice but not Gpr37-/- mice. Finally, chronic pain was associated with depression and anxiety, and NPD1 treatment mitigated these chronic pain complications through GPR37. Thus, through modulation of demyelination, diverse responses of glial cells, and neuroinflammation, the NPD1/GPR37 axis serves as a protective mechanism and a therapeutic target against painful traumatic brain injury and its complications.

Human brain development is highly regulated by several spatiotemporal processes, which disruption can result in severe neurological disorders. Emerging evidence highlights the pivotal role of mitochondrial function as one of these fundamental pathways involved in neurodevelopment. Our study investigates the role of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) protein in cortical neurogenesis and mitochondrial activity, since mutations in the HPDL gene are associated with SPG83, a childhood-onset form of hereditary spastic paraplegia characterized by corticospinal tract degeneration and cortical abnormalities. Starting from mutant neuroblastoma cells, we demonstrated that HPDL is essential to mitochondrial respiratory chain supercomplex assembly and cellular redox balance. Moreover, transcriptomic analyses revealed dysregulated pathways related to neurogenesis, implicating HPDL role in early cortical development. To further elucidate the role of HPDL, we generated cortical neurons and organoids from SPG83 patient-derived induced pluripotent stem cells. Mutant cells exhibited premature neurogenesis at early differentiation stages, likely leading to depletion of cortical progenitors, as evidenced by decreased proliferation, slight increase of apoptosis, and unbalanced cortical type composition at later stages. Furthermore, cortical organoids derived from SPG83 patients showed impaired growth, reminding microcephaly observed in severe cases. In addition, mitochondrial morpho-functional characterization in mutant neurons confirmed disruption of OxPhos chain functionality and increased ROS generation rate. Treatment of cortical cells with two antioxidant compounds, could partially revert premature neurogenesis. In conclusion, our findings reveal a critical role for HPDL in coordinating cortical progenitor proliferation, neurogenesis, and mitochondrial function. These insights shed light on a mechanistical understanding of SPG83 pathology and underscore the therapeutic potential of targeting oxidative stress in this and related neurological disorders.

Caspases are required for execution of apoptosis. However, in their absence, signals that typically induce apoptosis can still result in cell death. Our laboratory previously demonstrated that Casp3-deficient mouse embryonic fibroblasts (MEFs) have increased fibronectin (FN) secretion, and an adhesion-dependent survival advantage compared to wild type (WT) MEFs. Here, we show that FN is required for survival of Casp3-deficient MEFs following serum withdrawal. Furthermore, when FN is silenced, serum withdrawal-induced death is caspase-independent. However, procaspase-7 is cleaved, suggesting that MOMP is taking place. Indeed, in the absence of FN, cytochrome c release is increased following serum withdrawal in Casp3-deficient MEFs. Yet death does not correspond to cytochrome c release in Casp3-deficient MEFs. This is true both in the presence and absence of FN. Additionally, caspase-independent death is inhibited by Bcl-XL overexpression. These findings suggest that Bcl-XL is not inhibiting death through regulation of Bax/Bak insertion into the mitochondria, but through a different mechanism. One such possibility is autophagy and induction of autophagy is associated with caspase-independent death in Casp3-deficient cells. Importantly, when ATG5 is ablated in Casp3-deficient cells, autophagy is blocked and death is largely inhibited. Taken together, our data indicate that Casp3-deficient cells incapable of undergoing canonical serum withdrawal-induced apoptosis, are protected from autophagy-dependent death by FN-mediated adhesion.

Ferroptosis is a distinct form of regulated cell death promoted by iron-dependent lipid peroxidation. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. Although mitochondrial dysfunction contributes to metabolic reprogramming in cancer cells, its role in ferroptosis remains to be identified. We identified that the mitochondrial genome encodes 13 miRNAs (mitomiRs) that are highly expressed in breast cancer cell lines and patient-derived tumor samples. Expression analysis revealed that mitomiRs are upregulated in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Interestingly, 11 out of the 13 mitomiRs bind to the 3'UTR of zinc finger E-box-binding homeobox 1 (ZEB1), a transcription factor, involved in epithelial to mesenchymal transition (EMT) in breast cancer. Using mitomiR-3 mimic, inhibitor and sponges, we confirmed that mitomiR-3 indeed regulate ZEB1 expression in TNBC cells. Increased mesenchymal features in TNBC contributed to vulnerability to pro-ferroptotic metabolic reprogramming sensitizing to cell death in in vitro and in vivo models. Some of the challenges associated with pro-ferroptotic drugs includes lack of cancer cell specificity, low targeting ability, normal tissue toxicity contributing to their limited clinical application as cancer therapeutics. Here, we identified mitomiRs which are highly expressed in TNBC subtypes with low expression in normal breast cells making them an ideal candidate for selective inhibition for targeted therapy. Further, we demonstrated that the inhibition of mitomiRs in triple-negative breast cancer cells promote pro-ferroptotic metabolic reprogramming which can be exploited as novel vulnerability for targeted ferroptotic induction in cancer cells avoiding the normal tissue toxicity. Collectively, our results indicate a novel mechanism of mitochondrial miRNA mediated ferroptosis sensitivity in TNBC subtypes which could be exploited to develop potential miRNA-based therapeutics.

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.

The lysosomal damage response is important for the maintenance of cellular homeostasis. Although the mechanisms underlying the repair and autophagic elimination of damaged lysosomes have been elucidated, the early signal transduction pathways and genes induced in response to lysosomal damage remain elusive. We performed transcriptome and proteome analyses and found that the TAB-TAK1- IKK-NF-{kappa}B axis is activated by K63-linked ubiquitin chains that accumulate on damaged lysosomes. This activates the expression of various transcription factors and cytokines that promote anti-apoptosis and intercellular signaling. The findings highlight the crucial role of ubiquitin-regulated signal transduction and gene expression in cell survival and cell-cell communication in response to lysosomal damage. The results suggest that the ubiquitin system is not only involved in the removal of damaged lysosomes by lysophagy, but also functions in the activation of cellular signaling for cell survival.

The microRNAs miR-15a and miR-16 are key regulators of the anti-apoptotic oncogene BCL2, playing a significant role in tumorigenesis. These miRNAs function as tumor suppressors by directly targeting BCL2, whose overexpression contributes to cell survival and resistance to therapy in multiple malignancies, including chronic lymphocytic leukemia (CLL). The downregulation or deletion miR-15a/miR-16-1 cluster located on chromosome 13q occurs in about 50% of CLL patients and leads to the overexpression of the oncogenic BCL2, contributing to the survival and proliferation of cancer cells. In this confirmatory study, we provide additional evidence supporting the mechanism by which these miRNAs mediate the inhibition of BCL2 translation, leading to reduced levels of BCL2 protein with no significant effect on BCL2 mRNA degradation. This mechanism has been previously established as a critical pathway in the regulation of apoptosis, particularly in cancer cells where BCL2 overexpression is often associated with resistance to cell death. Our findings reinforce the notion that miRNAs, such as miR-15 and miR-16, bind to the 3-UTR of BCL2 messenger RNA (mRNA), specifically repressing its translation without inducing mRNA degradation. The results from our study align with previous research, confirming that the miRNA-mediated inhibition of BCL2 translation serves as a precise regulatory mechanism that targets protein synthesis rather than mRNA stability. These findings highlight the role of miRNAs in fine-tuning post-transcriptional gene regulation, offering a targeted approach to downregulate oncogenic proteins like BCL2 without disrupting the underlying mRNA, which could be leveraged for more refined therapeutic strategies.

The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated post-mitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondrial dynamics and quality control appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, due to haploinsufficiency in the mitochondrial optic-atrophy-type-1 (OPA1) protein. While in Dominant Optic Atrophy (DOA) models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected hippocampal adult-born neurons showed a decrease in mitochondrial content. Remarkably, modulating mitochondrial function through voluntary exercise or pharmacological treatment restored spatial memory. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, early amplification of mitochondrial function appears beneficial for late-onset neurodegenerative diseases.

The Kv8.1 potassium ion channel encoded by the KCNV1 gene is a "silent" subunit whose biological function is unknown. In ALS patient-derived motor neurons carrying SOD1(A4V) and C9orf72 mutations, its expression is highly reduced, yielding increased vulnerability to cell death without a change in motor neuronal firing. Our data suggests that Kv8.1 modulates Kv2 channel function to impact neuronal metabolism and lipid/protein transport pathways, but not excitability.

Triple-negative breast cancer (TNBC) is an aggressive subtype representing approximately 10%-20% of breast cancers and lacking effective therapies. TRPML1, which is a lysosomal Ca2+ release channel upregulated in TNBC, promotes TNBC tumor growth. Here we show a novel crosstalk between lysosomes and mitochondria mediated by TRPML1 in TNBC. TRPML1 is required for the maintenance of mitochondrial function and reactive oxygen species (ROS) homeostasis. TRPML1 knockdown inhibits TNBC mitochondrial respiration, glycolysis and ATP production, leading to reduced proliferation, promotion of cell cycle arrest and apoptosis with enhanced global and mitochondrial ROS. Further, TRPML1 downregulation enhances the cytotoxic effect of Doxorubicin in TNBC cells. Our data reveal a hitherto unknown link between lysosomal TRPML1 channels and mitochondrial metabolism and suggest that TRPML1 inhibition in combination with established chemotherapies could be an effective strategy against TNBC tumors.

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the P73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using several colorectal cancer cell lines, we show here that oxaliplatin treatment led to a dramatic core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of P73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed an antagonistic with oxaliplatin in co-treatments. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and P53 activity pushes cells towards apoptosis.