Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis.
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ABSTRACT:
SUBMITTER: Adeshakin FO
PROVIDER: S-EPMC8779336 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors.
| S-EPMC4947665 | biostudies-literature
Project description:Anoikis is a mode of apoptotic cell death, consequential to insufficient cell-matrix interactions and a critical player in tumor angiogenesis and metastasis. The events involved in tumor cell progression toward metastasis potential are mediated by integrins, which upon engagement with components of the extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting apoptotic players is of immense therapeutic significance since resistance to apoptosis is not only critical in conferring therapeutic failure to standard treatment strategies, but anoikis (apoptosis upon loss of anchorage and detachment from ECM) also plays an important role in angiogenesis and metastasis. The ability to survive in the absence of adhesion to the ECM, enables tumor cells to disseminate from the primary tumor site, invade a distant site and establish a metastatic lesion. Tumor cells can escape from detachment-induced apoptosis by controlling anoikis pathways, including the extrinsic death receptor pathway and the ECM-integrin mediated cell survival pathway. Considering the functional promiscuity of individual signaling effectors, it is critical to dissect the molecular networks mechanistically driving tumor cells to evade anoikis and embark on a metastatic spread. Resistance to die via anoikis dictates tumor cell survival and provides a molecular basis for therapeutic targeting of metastatic prostate cancer. Further dissection of critical anoikis signaling events will enable the therapeutic optimization of anoikis targeting to impair prostate cancer metastasis prior to its initiation. This review will discuss the molecular understanding of anoikis regulation in the tumor microenvironment and the in vivo pharmacological implementation of a novel class of antitumor-drugs to optimize apoptotic-based therapeutic targeting, bypassing anoikis-resistance to impair prostate cancer progression to metastasis. Potential combination strategies targeting tumor vascularity (via anoikis) and impairing tumor initiation (via "classic" apoptosis), provide strong therapeutic promise for metastatic prostate cancer by preventing the onset of metastasis.
| S-EPMC2988681 | biostudies-other
Project description:Evasion of extracellular matrix detachment-induced apoptosis ('anoikis') is a defining characteristic of metastatic tumor cells. The ability of metastatic carcinoma cells to survive matrix detachment and escape anoikis enables them to disseminate as viable circulating tumor cells and seed distant organs. Here we report that ?B-crystallin, an antiapoptotic molecular chaperone implicated in the pathogenesis of diverse poor-prognosis solid tumors, is induced by matrix detachment and confers anoikis resistance. Specifically, we demonstrate that matrix detachment downregulates extracellular signal-regulated kinase (ERK) activity and increases ?B-crystallin protein and messenger RNA (mRNA) levels. Moreover, we show that ERK inhibition in adherent cancer cells mimics matrix detachment by increasing ?B-crystallin protein and mRNA levels, whereas constitutive ERK activation suppresses ?B-crystallin induction during matrix detachment. These findings indicate that ERK inhibition is both necessary and sufficient for ?B-crystallin induction by matrix detachment. To examine the functional consequences of ?B-crystallin induction in anoikis, we stably silenced ?B-crystallin in two different metastatic carcinoma cell lines. Strikingly, silencing ?B-crystallin increased matrix detachment-induced caspase activation and apoptosis but did not affect cell viability of adherent cancer cells. In addition, silencing ?B-crystallin in metastatic carcinoma cells reduced the number of viable circulating tumor cells and inhibited lung metastasis in two orthotopic models, but had little or no effect on primary tumor growth. Taken together, our findings point to ?B-crystallin as a novel regulator of anoikis resistance that is induced by matrix detachment-mediated suppression of ERK signaling and promotes lung metastasis. Our results also suggest that ?B-crystallin represents a promising molecular target for antimetastatic therapies.
| S-EPMC4537846 | biostudies-literature
Project description:Normal cells require adhesion to extracellular matrix for survival. Cell detachment causes a drastic increase in reactive oxygen species (ROS) that promotes anoikis. In the present study, we observed that upon detachment from matrix, human mammary epithelial cells strongly upregulate manganese superoxide dismutase (MnSOD, or SOD2), a principal mitochondrial antioxidant enzyme that detoxifies ROS through dismutation of superoxide. Induction of MnSOD by cell detachment is dependent on the NF?B transcription factor. Detachment of mammary epithelial cells potently increases mitochondrial superoxide levels, which are further elevated by depletion of MnSOD in suspended cells. Consequently, cells depleted of MnSOD are hypersensitive to matrix detachment and exhibit increased anoikis. These results suggest that detachment-induced MnSOD counters mitochondrial superoxide accumulation and confers anoikis resistance. Taken together with our previous finding that detached cells evade excessive ROS production by attenuating oxidative metabolism of glucose, we conclude that mammary epithelial cells coordinate their responses to detachment through increasing MnSOD and decreasing ROS generation from mitochondrial glucose oxidation, thereby mitigating anoikis. Anoikis is a barrier to tumor metastasis. Indeed, MnSOD expression is elevated in human breast cancer metastases compared with primary tumors. Expression of MnSOD correlates with histologic tumor grades in human cancer and contributes to cancer cell's resistance to anoikis. Our study suggests that inhibition of ROS detoxification coupled with stimulation of glucose oxidative metabolism may be an efficient strategy to enhance anoikis and block metastasis.
| S-EPMC3734828 | biostudies-other
Project description:Targeted inhibition of mitochondrial oxidative phosphorylation (OXPHOS) complex generation is an emerging and promising cancer treatment strategy, but limited targets and specific inhibitors have been reported. Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is an atypical RNA-binding protein that regulates the stability of all 13 mitochondrial DNA-encoded mRNA (mt-mRNA) and thus participates in the synthesis of the OXPHOS complex. LRPPRC is also a prospective therapeutic target for lung adenocarcinoma, serving as a promising target for OXPHOS inhibition. In this study, we identified Demethylzeylasteral (T-96), a small molecule extracted from the Chinese herb Tripterygium wilfordii Hook. f., as a novel inhibitor of LRPPRC. T-96 directly bound to the RNA-binding domain of LRPPRC, inhibiting its interaction with mt-mRNA. This led to instability in both mt-mRNA and LRPPRC protein. Treatment with T-96 significantly reduced the mRNA and protein levels of the OXPHOS complex. As a consequence of LRPPRC inhibition, T-96 treatment induced a defect in the synthesis of the OXPHOS complex, inhibiting mitochondrial aerobic respiration and ATP synthesis. Moreover, T-96 exhibited potent antitumor activity for lung adenocarcinoma in vitro and in vivo, and the antitumor effect of T-96 was dependent on LRPPRC expression. In conclusion, this study not only identified the first traditional Chinese medicine monomer inhibitor against OXPHOS complex biosynthesis as well as a novel target of Demethylzeylasteral, but also shed light on the unique antitumor mechanism of bioactive compounds derived from traditional Chinese medicine.
2024-10-09 | GSE279114 | GEO
Project description:Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death, and the survival of ECM-detached cells is one of the prerequisites for the metastatic cascade. Ferroptosis, a form of iron-dependent programmed cell death, has recently been found to be involved in matrix-detached cancer cells. However, the molecular mechanisms by which ECM-detached cells escape ferroptosis are not fully understood. Here, we observed that cell migration-inducing protein (CEMIP) upregulation facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake in prostate cancer (PCa) cells. Meanwhile, silencing CEMIP causes it to lose its ability to promote cystine uptake and inhibit ferroptosis. Mechanistically, the interaction of CEMIP with inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca2+ ) leakage from the endoplasmic reticulum, activating calcium/calmodulin-dependent protein kinase II (CaMKII), which further facilitates nuclear factor erythroid 2-related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Our findings delineate a novel role of CEMIP in ferroptosis resistance during ECM detachment and provide new insights into therapeutic strategies for metastatic PCa.
| S-EPMC9207355 | biostudies-literature
Project description:Anoikis resistance is an important mechanism that mediates tumor metastasis. Studies have found that Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) promotes the occurrence, development, and metastasis of nasopharyngeal carcinoma (NPC). However, the related mechanism, especially whether LMP1 is involved in NPC metastasis through anoikis resistance, has not yet been elucidated. In present study, we showed that LMP1 enhanced the ability of NPC cells to resist anoikis by upregulating neurotrophic tyrosine kinase receptor type 2 (NTRK2 or TrkB) expression through NF-?B signaling and promoted the migration and invasion of NPC cells. After knockdown of NTRK2, the p-ERK and p-AKT in NPC cells were inhibited, and twist expression was further reduced, resulting in upregulation of E-cadherin expression and downregulation of vimentin expression. Subsequently, the results of a xenograft experiment showed that inhibiting NTRK2 could reduce LMP1-mediated NPC metastasis in vivo. In summary, these findings demonstrated that EBV-LMP1 upregulates twist expression to promote epithelial-mesenchymal transition (EMT) through the NTRK2-mediated AKT/ERK signaling pathway, thus mediating anoikis resistance and promoting NPC metastasis. These data will provide new molecular markers and potential targets for NPC metastasis.
| S-EPMC7407352 | biostudies-literature
Project description:BACKGROUND:Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis. METHODS:We analyzed the association of collagen XIII expression with breast cancer development and metastasis using published gene expression profiles generated from human breast cancer tissues. Utilizing gain- and loss- of function approaches and 3D culture assays, we investigated roles of collagen XIII in regulating invasive tumor growth. Using the tumorsphere/mammosphere formation assay and the detachment cell culture assay, we determined whether collagen XIII enhances cancer cell stemness and induces anoikis resistance. We also inhibited collagen XIII signaling with ?1 integrin function-blocking antibody. Finally, using the lung colonization assay and the orthotopic mammary tumor model, we investigated roles of collagen XIII in regulating breast cancer colonization and metastasis. Cox proportional hazard (log-rank) test, two-sided Student's t-test (two groups) and one-way ANOVA (three or more groups) analyses were used in this study. RESULTS:Collagen XIII expression is significantly higher in human breast cancer tissue compared with normal mammary gland. Increased collagen XIII mRNA levels in breast cancer tissue correlated with short distant recurrence free survival. We showed that collagen XIII expression promoted invasive tumor growth in 3D culture, enhanced cancer cell stemness, and induced anoikis resistance. Collagen XIII expression induced ?1 integrin activation. Blocking ?1 integrin activation significantly reduced collagen XIII-induced invasion and mammosphere formation. Importantly, silencing collagen XIII in MDA-MB-231 cells reduced lung colonization and metastasis. CONCLUSIONS:Our results demonstrate a novel function of collagen XIII in promoting cancer metastasis, cell invasion, and anoikis resistance.
| S-EPMC6167877 | biostudies-other
Project description:Hyperphosphorylated tau proteins accumulate in the paired helical filaments of neurofibrillary tangles seen in such tauopathies as Alzheimer's disease. In the present paper we show that tau turnover is dependent on degradation by the proteasome (inhibited by MG132) in HT22 neuronal cells. Recombinant human tau was rapidly degraded by the 20 S proteasome in vitro, but tau phosphorylation by GSK3beta (glycogen synthase kinase 3beta) significantly inhibited proteolysis. Tau phosphorylation was increased in HT22 cells by OA [okadaic acid; which inhibits PP (protein phosphatase) 1 and PP2A] or CsA [cyclosporin A; which inhibits PP2B (calcineurin)], and in PC12 cells by induction of a tet-off dependent RCAN1 transgene (which also inhibits PP2B). Inhibition of PP1/PP2A by OA was the most effective of these treatments, and tau hyperphosphorylation induced by OA almost completely blocked tau degradation in HT22 cells (and in cell lysates to which purified proteasome was added) even though proteasome activity actually increased. Many tauopathies involve both tau hyperphosphorylation and the oxidative stress of chronic inflammation. We tested the effects of both cellular oxidative stress, and direct tau oxidative modification in vitro, on tau proteolysis. In HT22 cells, oxidative stress alone caused no increase in tau phosphorylation, but did subtly change the pattern of tau phosphorylation. Tau was actually less susceptible to direct oxidative modification than most cell proteins, and oxidized tau was degraded no better than untreated tau. The combination of oxidative stress plus OA treatment caused extensive tau phosphorylation and significant inhibition of tau degradation. HT22 cells transfected with tau-CFP (cyan fluorescent protein)/tau-GFP (green fluorescent protein) constructs exhibited significant toxicity following tau hyperphosphorylation and oxidative stress, with loss of fibrillar tau structure throughout the cytoplasm. We suggest that the combination of tau phosphorylation and tau oxidation, which also occurs in tauopathies, may be directly responsible for the accumulation of tau aggregates.
| S-EPMC1698600 | biostudies-other
Project description:Uneven oxygen supply in solid tumors leads to hypoxic and normoxic regions. Hypoxic cells exhibit increased secretion of lactate, which creates an acidic tumor microenvironment (TME). This acidic TME is positively associated with tumor metastasis. Despite the increased metastatic capacity of hypoxic cells, they are located relatively further away from the blood vessels and have limited access to the circulatory system. Studies have shown that cancer stem cells (CSCs) are enriched for tumor metastasis-initiating cells and generally undergo aerobic respiration, which could be enhanced by lactate. We therefore hypothesized that TME-derived lactate may promote the metastasis of normoxic CSCs. In the present study, the abundance of hypoxic and normoxic CSCs was analyzed in primary CRC tumors. It was found that the proportion of normoxic CSCs was positively associated with tumor stage. Using two human CRC cell lines, LoVo and SW480, and a patient-derived xenograft (XhCRC), it was found that treatment with lactate promoted normoxic CSC metastasis. Metabolism analysis indicated that, upon treatment with lactate, oxidative phosphorylation (OXPHOS) activity in normoxic CSCs was enhanced, whereas hypoxic CSCs were rarely altered. At the molecular level, the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of lactate oxidation, was found to be elevated in normoxic CSCs. Furthermore, PGC-1α knockdown markedly reduced the metastatic potential of normoxic CSCs. Notably, both the PGC-1α-mediated OXPHOS activity and metastatic potential were impaired when hypoxia-inducible factor-1α (HIF-1α) was activated in normoxic CSCs. Together, these findings provide a therapeutic strategy against tumor metastasis through the targeting of PGC-1α and, thus, the suppression of lactate-feeding OXPHOS in normoxic CSCs may improve the therapeutic benefit of patients with cancer, particularly CRC.
| S-EPMC9329320 | biostudies-literature