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[Display omitted] • Radiotherapy promotes the binding of CDK2 and TRIM32, thus leading to increased CDK2-dependent phosphorylation of TRIM32 at serines 328 and 339. • Cis-trans isomerization of TRIM32 recruit PIN1, which resulting in importin α3 binding to TRIM32 and contributing to its nuclear translocation. • Nuclear TRIM32 inhibits TC45-dephosphorylated STAT3, Leading to increased transcription of STAT3 and radioresistance in triple-negative breast cancer (TNBC). • Regulating the CDK2/TRIM32/STAT3 pathway is a promising strategy for reducing radioresistance in TNBC, which is important for TNBC therapy. Despite radiotherapy being one of the major treatments for triple-negative breast cancer (TNBC), new molecular targets for its treatment are still required due to radioresistance. CDK2 plays a critical role in TNBC. However, the mechanism by which CDK2 promotes TNBC radioresistance remains to be clearly elucidated. We aimed to elucidate the relationship between CDK2 and TRIM32 and the regulation mechanism in TNBC. We performed immunohistochemical staining to detect nuclear TRIM32, CDK2 and STAT3 on TNBC tissues. Western blot assays and PCR were used to detect the protein and mRNA level changes. CRISPR/Cas9 used to knock out CDK2. shRNA-knockdown and transfection assays also used to knock out target genes. GST pull-down analysis, immunoprecipitation (IP) assay and in vitro isomerization analysis also used. Tumorigenesis studies also used to verify the results in vitro. Herein, tripartite motif-containing protein 32 (TRIM32) is revealed as a substrate of CDK2. Radiotherapy promotes the binding of CDK2 and TRIM32, thus leading to increased CDK2-dependent phosphorylation of TRIM32 at serines 328 and 339. This causes the recruitment of PIN1, involved in cis–trans isomerization of TRIM32, resulting in importin α3 binding to TRIM32 and contributing to its nuclear translocation. Nuclear TRIM32 inhibits TC45-dephosphorylated STAT3, Leading to increased transcription of STAT3 and radioresistance in TNBC. These results were validated by clinical prognosis confirmed by the correlative expressions of the critical components of the CDK2/TRIM32/STAT3 signaling pathway. Our findings demonstrate that regulating the CDK2/TRIM32/STAT3 pathway is a promising strategy for reducing radioresistance in TNBC. [ABSTRACT FROM AUTHOR]

Dysregulation of receptor tyrosine kinases is implicated in cancer development. This study aimed to investigate the nuclear translocation of Axl, a membrane protein and receptor tyrosine kinase in cancer malignancy. We examined Axl's entry into the cell nucleus and validated it with the nuclear export inhibitor leptomycin. Transfection experiments with mutated nuclear localization signals were conducted to assess the impact of reduced nuclear Axl levels on cancer cell malignancy. Additionally, we evaluated the effects of decreased nuclear Axl on sensitivity to radiation and cisplatin, a chemotherapeutic drug. In the present study, we observed nuclear translocation of Axl in cancer cells. Reducing nuclear Axl levels led to a decrease in cancer cell malignancy. This nuclear translocation was further validated using a nuclear export inhibitor, leptomycin. Additionally, transfection experiments with mutated nuclear localization signals confirmed the functional significance of Axl's nuclear localization. Notably, decreased nuclear Axl levels also increased the sensitivity of cancer cells to radiation and cisplatin treatment. This study suggests that Axl's nuclear translocation plays a significant role in cancer malignancy. Targeting Axl's nuclear localization could offer a potential strategy to inhibit cancer progression and improve the efficacy of radiation and chemotherapy treatments. [ABSTRACT FROM AUTHOR]

Skin damage caused by exposure to ultraviolet (UV) light has been well documented clinically and histologically. Dopamine receptor D2 (DRD2) possesses various biological functions. However, no study has reported the possible association of DRD2 with UV-induced skin damage. We established DRD2 conditional knockout and UV damage models in this work. The results showed that DRD2 played an important role in the treatment of UV-induced skin damage. The findings of the molecular mechanism study revealed that the internalization of DRD2 after activation can stabilize nuclear factor erythroid 2-related factor 2 (Nrf2). However, the entry of Nrf2 into the nucleus did not increase. We prepared and characterized hyaluronic acid (HA)-coated mesoporous polydopamine (MPDA) nanoparticles (H@P@M). HA facilitated skin epidermal penetration of the nanoparticles to reach the site of inflammation smoothly. Meanwhile, MPDA activated DRD2 internalization to stabilize Nrf2. The release of prunetin inhibited the interaction of Kelch-like ECH-associated protein 1 with Nrf2 and promoted the nuclear translocation of Nrf2. In summary, this study unveiled that in skin inflammation, H@P@M activated and internalized DRD2, which subsequently formed a protein complex with arrestin beta 1–ubiquitin specific protease 8 (USP8)–Nrf2. Deubiquitination was performed to stabilize Nrf2 while promoting the nuclear translocation of Nrf2 to exert anti-inflammatory and antioxidant functions. Skin is the body's largest physical barrier, always protecting the body from the interference of the external environment. However, excessive exposure to ultraviolet rays in the sun can cause skin inflammation, leading to skin erythema, itching, edema and pain, which can be troublesome in our daily lives. The complex mechanism of skin inflammation caused by ultraviolet radiation has not been fully clarified. In this study, the role of DRD2 in UV-induced skin inflammation was explored, and nano-composite particles HA@Prunetin@MPDA, which act on multiple targets in the anti-inflammatory pathway of DRD2, were developed to maximize the effect of the drug. It provides a new way to treat skin inflammation caused by UV. [Display omitted] [ABSTRACT FROM AUTHOR]

Yes-associated protein (YAP) has been widely studied as a mechanotransducer in many cell types, but its function in cartilage is controversial. The aim of this study was to identify the effect of YAP phosphorylation and nuclear translocation on the chondrocyte response to stimuli relevant to osteoarthritis (OA). Cultured normal human articular chondrocytes from 81 donors were treated with increased osmolarity media as an in vitro model of mechanical stimulation, fibronectin fragments (FN-f) or IL-1β as catabolic stimuli, and IGF-1 as an anabolic stimulus. YAP function was assessed with gene knockdown and inhibition by verteporfin. Nuclear translocation of YAP and its transcriptional co-activator TAZ and site-specific YAP phosphorylation were determined by immunoblotting. Immunohistochemistry and immunofluorescence to detect YAP were performed on normal and OA human cartilage with different degrees of damage. Chondrocyte YAP/TAZ nuclear translocation increased under physiological osmolarity (400 mOsm) and IGF-1 stimulation, which was associated with YAP phosphorylation at Ser128. In contrast, catabolic stimulation decreased the levels of nuclear YAP/TAZ through YAP phosphorylation at Ser127. Following YAP inhibition, anabolic gene expression and transcriptional activity decreased. Additionally, YAP knockdown reduced proteoglycan staining and levels of type II collagen. Total YAP immunostaining was greater in OA cartilage, but YAP was sequestered in the cytosol in cartilage areas with more severe damage. YAP chondrocyte nuclear translocation is regulated by differential phosphorylation in response to anabolic and catabolic stimuli. Decreased nuclear YAP in OA chondrocytes may contribute to reduced anabolic activity and promotion of further cartilage loss. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning (IPC) is a potential intervention known to protect the heart against ischemia/reperfusion injury, but its role in the no-reflow phenomenon that follows reperfusion is unclear. Dihydrotanshinone I (DT) is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC. Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation (OGD), but the protection was prevented by a ROS scavenger. In addition, DT administration protected the heart against isoprenaline challenge. Mechanistically, PKM2 reacted to transient ROS via oxidization at Cys423/Cys424, leading to glutathionylation and nuclear translocation in dimer form. In the nucleus, PKM2 served as a co-factor to promote HIF-1 α -dependent gene induction, contributing to adaptive responses. In mice subjected to permanent coronary ligation, cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection, which was rescued by overexpression of wild-type Pkm2 , rather than Cys423/424-mutated Pkm2. In conclusion, PKM2 is sensitive to oxidation, and subsequent glutathionylation promotes its nuclear translocation. Although IPC has been viewed as a protective means against reperfusion injury, our study reveals its potential role in protection of the heart from no-reflow ischemia. Dihydrotanshinone I induces mild ROS generation and facilitates the nuclear translocation of PKM2 via glutathionylation. Glutathionylated PKM2 stabilizes HIF-1 α and potentiates the transcriptional activity of HIF-1 α , contributing to preconditioning protection. [Display omitted] [ABSTRACT FROM AUTHOR]

Rescuing cells from stress damage emerges a potential therapeutic strategy to combat myocardial infarction. Protocatechuic aldehyde (PCA) is a major phenolic acid in Chinese herb Danshen (Salvia miltiorrhiza root). This study investigated whether PCA regulated nuclear pyruvate kinase isoform M2 (PKM2) function to protect cardiomyocytes. In rats subjected to isoprenaline, PCA attenuated heart injury and protected cardiomyocytes from apoptosis. Through DARTS and CETSA assays, we identified that PCA bound and promoted PKM2 nuclear translocation in cardiomyocytes exposed to oxygen/glucose deprivation (OGD). In the nucleus, PCA increased the binding of PKM2 to β -catenin via preserving PKM2 acetylation, and the complex, in cooperation with T-cell factor 4 (TCF4), was required for transcriptional induction of genes encoding anti-apoptotic proteins, contributing to rescuing cardiomyocyte survival. In addition, PCA ameliorated mitochondrial dysfunction and prevented mitochondrial apoptosis dependent on PKM2. Consistently, PCA increased the binding of PKM2 to β -catenin, improved heart contractive function, normalized heart structure and attenuated oxidative damage in mice subjected to artery ligation, but the protective effects were lost in Pkm2 -deficient heart. Together, we showed that PCA regulated nuclear PKM2 function to rescue cardiomyocyte survival via β -catenin/TCF4 signaling cascade, suggesting the potential of pharmacological intervention of PKM2 shuttle to protect the heart. By direct interaction, protocatechuic aldehyde (PCA) promotes PKM2 nuclear localization, where it initiates PKM2/ β -catenin/TCF signaling cascades for transcriptional induction of genes and protecting cardiomyocytes against ischemic heart injury. [Display omitted] [ABSTRACT FROM AUTHOR]

Early and accurate diagnosis of prostate cancer (PCa) is extremely important, as metastatic PCa remains hard to treat. EWI‐2, a member of the Ig protein subfamily, is known to inhibit PCa cell migration. In this study, we found that EWI‐2 localized on both the cell membrane and exosomes regulates the distribution of miR‐3934‐5p between cells and exosomes. Interestingly, we observed that EWI‐2 is localized not only on the plasma membrane but also on the nuclear envelope (nuclear membrane), where it regulates the nuclear translocation of signaling molecules and miRNA. Collectively, these functions of EWI‐2 found in lipid bilayers appear to regulate PCa cell metastasis through the epidermal growth factor receptor‐mitogen‐activated protein kinase‐extracellular‐signal‐regulated kinase (EGFR‐MAPK‐ERK) pathway. Our research provides new insights into the molecular function of EWI‐2 on PCa metastasis, and highlights EWI‐2 as a potential PCa biomarker. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Vitamin D receptor (VDR) belongs to the nuclear receptor superfamily and exerts a renoprotective effect through inhibiting fibrosis. Microtubule-associated protein 1 light chain 3 (LC3), a key regulator of autophagy, is abundant in the nucleus, although its primary function is in the cytoplasm. The role of nuclear LC3 and the mechanism by which LC3 shuttles between the cytoplasm and nucleoplasm has not been fully elucidated. We found that LC3 binds to VDR in an LC3-interacting region (LIR)-independent manner and promotes the nuclear translocation of VDR. Further study indicated that LC3 promotes the formation of the VDR:retinoid X receptor (RXR) heterodimer and inhibits fibrogenic genes expression in HK-2 cells induced by high glucose. Our result demonstrates that LC3 is a negative regulator of high glucose-induced fibrogenic genes expression through its ability to promote VDR signaling. • LC3 promotes the nuclear translocation of the VDR. • LC3 binds the VDR in an LC3-interacting region (LIR)-independent manner. • LC3 promotes the formation of the VDR:retinoid X receptor (RXR) heterodimer. • LC3 inhibits fibrogenic genes expression in HK-2 cells induced by high glucose. [ABSTRACT FROM AUTHOR]

Introduction Accumulation of hyperphosphorylated tau and the disruption of microtubules are correlated with synaptic loss and pathology of Alzheimer's disease (AD). Impaired cognitive function and pathology of AD is correlated with this lesion. This review looks at the mechanism of neurodegeneration, the prion-like behavior of tau in its interaction with normal MAPs in correlation with tau hyperphosphorylation. Methods We reviewed our work in the field as well as current literature that pertains to tau phosphorylation and the biological effects. Results Hyperphosphorylation of tau in AD, in vitro, in cells, or in animal models converts this protein into a prion-like protein that is able to propagate the altered conformation. Discussion These findings suggest that phosphorylation of tau is a critical event in neurodegeneration. The combination of phosphorylation sites can generate a gain of toxic function for tau. The mechanism of tau toxicity might involve not only the microtubule system but also interference with other cellular compartments such as the nucleus and the actin cytoskeleton. [ABSTRACT FROM AUTHOR]

Plants employ cell-surface-localized pattern recognition receptors (PRRs) to recognize immunogenic patterns and activate defenses. How these receptors regulate immune signaling in the nucleus is not well understood. Our previous studies showed that BIK1, a central kinase associated with PRRs, phosphorylates a plant-specific Gα protein called extra-large G protein 2 (XLG2) to positively regulate immunity. Here, we show that this phosphorylation promotes XLG2 nuclear translocation, which is essential for antibacterial immunity. XLG2 interacts with nuclear-localized MUT9-like kinases (MLKs) to regulate transcriptome programming. MLKs negatively regulate plant immunity in a kinase activity-dependent manner, whereas XLG2 promotes defense gene expression and antibacterial immunity likely by inhibiting MLK kinase activity. A C-terminal motif in MLKs is essential for the interaction with XLG2, and this motif is required for the XLG2-mediated defense activation. Together, our findings reveal a previously unknown pathway and mechanisms by which cell surface receptors regulate transcriptome during pathogen invasion. [Display omitted] • Immune-activated phosphorylation of XLG2 promotes nuclear translocation and immunity • XLG2 interacts with the nuclear protein kinases MLKs to co-regulate plant immunity • MLKs negatively regulate immunity in a kinase-dependent manner • XLG2 inhibits the kinase activity of MLKs to unlock defense gene expression Plant PRRs recognize molecular patterns to initiate defense, but how these receptors regulate nuclear immune signaling is unclear. Ma et al. reveal that PRR-mediated phosphorylation of XLG2 promotes the nuclear translocation of this Gα protein, where it binds and inhibits a family of kinase called MLKs, to activate immune signaling. [ABSTRACT FROM AUTHOR]

The ovarian-tumor-domain-containing deubiquitinases (OTUDs) block ubiquitin-dependent protein degradation and are involved in diverse signaling pathways. We discovered a rare OTUD3 c.863G>A mutation in a family with an early age of onset of diabetes. This mutation reduces the stability and catalytic activity of OTUD3. We next constructed an experiment with Otud3 −/− mice and found that they developed worse obesity, dyslipidemia, and insulin resistance than wild-type mice when challenged with a high-fat diet (HFD). We further found that glucose and fatty acids stimulate CREB-binding-protein-dependent OTUD3 acetylation, promoting its nuclear translocation, where OTUD3 regulates various genes involved in glucose and lipid metabolism and oxidative phosphorylation by stabilizing peroxisome-proliferator-activated receptor delta (PPARδ). Moreover, targeting PPARδ using a specific agonist can partially rescue the phenotype of HFD-fed Otud3 −/− mice. We propose that OTUD3 is an important regulator of energy metabolism and that the OTUD3 c.863G>A is associated with obesity and a higher risk of diabetes. [Display omitted] • OTUD3 c.863G>A in humans is associated with obesity and a higher risk of diabetes • OTUD3 regulates energy metabolism by blocking ubiquitin-dependent PPARδ degradation • Glucose and fatty acids evoke OTUD3 nuclear translocation by CBP-dependent acetylation • CBP-OTUD3 signaling pathway may be a novel regulatory mechanism for energy metabolism Zhou et al. report a new metabolic-syndrome-associated mutation in the OTUD3 deubiquitinase found in a MODY-like family. They discover that glucose and fatty acids can trigger translocation of OTUD3 to the nucleus, where it regulates energy metabolism by stabilizing PPARδ. [ABSTRACT FROM AUTHOR]

Objective: Protein kinase B (PKB/Akt), which is phosphorylated and activated by upstream activators, exerts critical neuroprotective effects by phosphorylating downstream targets after traumatic brain injury (TBI). Studies on the regulation of Akt will be crucial for our understanding of neuronal survival. The goal of this study is to investigate the effects of carboxyl-terminal modulator protein (CTMP) on phosphorylation of Akt and neurological function in a mouse model of TBI. Methods: Traumatic brain injury in mice was performed by a controlled cortical impact device. The expression of Akt, phospho-Akt, and CTMP was examined in the injured cortices by immunohistochemistry and Western blot analysis. To determine the effects of CTMP, small interfering RNAs (siRNAs) directed against CTMP were injected in mice with TBI, and the expression of phosphorylated Akt and neurological function were evaluated. Results: Phospho-Akt significantly increased at 4 hours post-TBI in the nucleus (P < 0.01) and remained at high levels until 72 hours after TBI, as shown by Western blot analysis. In the cytosol, the expression of phospho-Akt reached its peak at 4 hours post-TBI, but decreased markedly at 24 hours and maintained below pre-TBI levels until 72 hours post-TBI. Interestingly, the expression of CTMP significantly increased 4 hours after TBI (P < 0.01) and sustained those levels until 72 hours without dramatic changes. Treatment with CTMP siRNA effectively augmented the phosphorylation of Akt and significantly improved the neurological functional recovery up to 28 days post-TBI. Conclusion: We conclude that Akt is phosphorylated and translocated to nucleus after TBI to exert neuroprotective effects. However, CTMP is simultaneously triggered to inhibit the phosphorylation of Akt. Inhibition of CTMP by siRNA improves the recovery of neurological functions after TBI. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder (Thymelaeaceae). Methods: The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking. Results: Wikstroelide M potently inhibited different HIV-1 strains, including HIV-1IIIB, HIV-1A17, and HIV-19495, induced a cytopathic effect, with EC50 values ranging from 3.81 to 15.65 ng·mL−1. Wikstroelide M also had high inhibitory activities against HIV-2ROD and HIV-2CBL-20-induced cytopathic effects with EC50 values of 18.88 and 31.90 ng·mL−1. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with EC50 values ranging from 15.16 to 35.57 ng·mL−1. Wikstroelide M also potently inhibited HIV-1IIIB induced cytolysis in MT-4 cells, with an EC50 value of 9.60 ng·mL−1. The mechanistic assay showed that wikstroelide M targeted HIV-1 reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75. Conclusion: Wikstroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear translocation through disrupting the interaction between integrase and LEDGF/p75. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii provokes rapid and sustained nuclear translocation of the signal transducer and activator of transcription 6 (STAT6) in HeLa cells. We observed activation of STAT6 as early as 2 hr after infection with T. gondii by the nuclear translocation of fluorescence expressed from exogenously transfected pDsRed2-STAT6 plasmid and by the detection of phosphotyrosine-STAT6 in Western blot. STAT6 activation occurred only by infection with live tachyzoites but not by co-culture with killed tachyzoites or soluble T. gondii extracts. STAT6 phosphorylation was inhibited by small interfering RNA of STAT6 (siSTAT6). In view of the fact that STAT6 is a central mediator of IL-4 induced gene expression, activation of STAT6 by T. gondii infection resembles that infected host cells has been stimulated by IL-4 treatment. STAT1 was affected to increase the transcription and expression by the treatment of siSTAT6. STAT6 activation was not affected by any excess SOCS's whereas that with IL-4 was inhibited by SOCS-1 and SOCS-3. T. gondii infection induced Eotaxin- 3 gene expression which was reduced by IFN-γ. These results demonstrate that T. gondii exploits host STAT6 to take away various harmful reactions by IFN-γ. This shows, for the first time, IL-4-like action by T. gondii infection modulates microbicidal action by IFN-γ in infected cells. [ABSTRACT FROM AUTHOR]

Heparanase is an endo-β-glucuronidase that specifically cleaves heparan sulfate (HS) chains. Heparanase is involved in the process of metastasis and angiogenesis through the degradation of HS chains of the extracellular matrix and cell surface. Recently, we demonstrated that heparanase was localized in the cell nucleus of normal esophageal epithelium and esophageal cancer, and that its expression was correlated with cell differentiation. However, the nuclear function of heparanase remains unknown. To elucidate the role of heparanase in esophageal epithelial differentiation, primary human esophageal cells were grown in monolayer as well as organotypic cultures, and cell differentiation was induced. Expression of heparanase, HS, involucrin, and p27 was determined by immunostaining and Western blotting. SF4, a novel pharmacological inhibitor, was used to specifically inhibit heparanase activity. Upon esophageal cell differentiation, heparanase was translocated from the cytoplasm to the nucleus. Such translocation of heparanase appeared to be associated with the degradation of HS chains in the nucleus and changes in the expression of keratinocyte differentiation markers such as p27 and involucrin, whose induction was inhibited by SF4. Furthermore, these in vitro observations agreed with the expression pattern of heparanase, HS, involucrin, cytokeratin 13, and p27 in normal esophageal epithelium. Nuclear translocation of heparanase and its catalytic cleavage of HS may play a critical role in the differentiation of esophageal epithelial cells. Our study provides a novel insight into the role of heparanase in an essential differentiation process. [ABSTRACT FROM AUTHOR]

Hexavalent chromium [Cr(VI)] is a pervasive environmental pollutant that can enter the body through a variety of routes and cause organ toxicity, genetic damage, and cancer. Cr(VI)-induced apoptosis is a toxicant mechanism of Cr(VI). Studies have shown that Cr(VI) can induce p53-independent apoptosis, but the mechanisms are not fully understood. The intracellular calcium concentration affects cellular life. Apoptosis-inducing factor (AIF), a caspase-independent apoptotic effector, can induce DNA degradation. Using p53-null Hep3B cells, we investigated the effects of cytoplasmic calcium homeostasis and AIF on Cr(VI)-induced apoptosis. We found that 20 µM of Cr(VI) induced DNA damage and mitochondrial permeability transition pore (MPTP) openings, causing calcium overload that was accompanied by decreased Ca2+-Mg2+-ATPase and Na+-K+-ATP activities, downregulation of calmodulin (CaM) and Ca2+/CaM-dependent protein kinase II (CAMKII) mRNA, and increased expression of p-CaMKII/CaMKII protein. After treatment with calcium chelating agent BAPTA-AM, Cr(VI)-induced DNA damage, calcium overload, and apoptosis were reduced. AIF was released from the mitochondria and translocated into the nuclei. As the Cr(VI) treatment time progressed, the mRNA and protein expression of B cell lymphoma 2 (Bcl-2) and heat-shock protein 70 (HSP70) decreased, whereas the mRNA and protein expression of Bcl-2-associated X (Bax), cyclophilin A (CypA), and endonuclease G (EndoG) were upregulated. These results indicated that Cr(VI)-induced apoptosis of Hep3B cells (p53-null) was closely associated with calcium overload, and was accompanied by the activation of Ca2+/CaM/CaMKII signaling pathway. Besides, Cr(VI) triggered AIF nuclear translocation in Hep3B cells, accompanied by the changes in the levels of apoptosis-associated factors. These results provide additional experimental evidence of the molecular mechanisms involved in Cr(VI)-induced p53-independent apoptosis. • Hexavalent chromium induced p-53 independent apoptosis. • Calcium overload plays an important role in Cr(VI)-induced apoptosis of Hep3B cells. • Calcium chelator alleviate Cr(VI)-induced apoptosis. • Hexavalent chromium induced AIF nuclear translocation in Hep3B cells. [ABSTRACT FROM AUTHOR]