scholarly journals Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
S Michael Rothenberg ◽  
Kyle Concannon ◽  
Sarah Cullen ◽  
Gaylor Boulay ◽  
Alexa B Turke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Tumor Regression ◽  
Acquired Resistance ◽  
Ectopic Expression ◽  
Growth Factor Signaling ◽  
Drug Induced ◽  
Mutant Egfr

Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance.

scholarly journals Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells

2020 ◽  
Author(s):  
Kang Wang ◽  
Zhengyang Zhang ◽  
Hsiang-i Tsai ◽  
Yanfang Liu ◽  
Jie Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Amino Acid ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Branched Chain Amino Acid ◽  
Pancreatic Cancer Cells ◽  
Key Enzyme ◽  
Branched Chain

Abstract Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc– activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

Evaluation of indibulin, a novel tubulin targeting-agent, in combination with capecitabine, with mathematically optimized dose scheduling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2538-2538
Author(s):  
J. J. Lewis ◽  
M. D. Galsky ◽  
L. H. Camacho ◽  
D. M. Loesch ◽  
P. B. Komarnitsky ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Acquired Resistance ◽  
Optimal Schedule ◽  
Xenograft Model ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Drug Induced ◽  
Dose Levels

2538 Background: Indibulin (IDB) is a novel, orally available tubulin-targeting molecule that perturbs cancer cell migration and mitosis. It is active against taxane-resistant cell lines and is synergistic with 5-FU in vitro and in vivo. Two translational studies have been conducted: a Phase IB study of IDB in combination with capecitabine (CAP) in patients with advanced solid tumors, and mathematical modeling applying Norton-Simon models to breast carcinoma MX-1 xenografts to further develop Phase II dose. Methods: IDB is administered continuously starting at 400 mg BID. CAP is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID. IDB and CAP are escalated to MTD: IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks using RECIST. In the xenograft model indibulin is administered at dose levels from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma. Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the efficacy/toxicity ratio. Results: To date, 7 patients have been treated and are evaluable for safety. Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are evaluable for efficacy and all have stable disease (3 for 6 cycles, 1 for 3 cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, anorexia, and headache. Neither DLTs nor grade ≥3 AEs have been observed. In MX-1 xenografts, indibulin demonstrates linear dose-efficacy relationship over the range of 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser effects over the next 5 days to a peak of efficacy at day 10 Conclusions: IDB + CAP is well tolerated, without neurotoxicity. There is preliminary evidence of clinical activity even with this sub-optimal, continuous schedule of IDB. Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug-induced toxicity. Pre- clinical evaluation in a breast cancer model supports an intermittent dosing schedule to further increase the activity of IDB. [Table: see text]

scholarly journals Calcium Binding of ARC Mediates Regulation of Caspase 8 and Cell Death

2004 ◽  
Vol 24 (22) ◽  
pp. 9763-9770 ◽  
Author(s):  
Dong-Gyu Jo ◽  
Joon-Il Jun ◽  
Jae-Woong Chang ◽  
Yeon-Mi Hong ◽  
Sungmin Song ◽  
...  
Keyword(s):  
Cell Death ◽  
Calcium Binding ◽  
Ectopic Expression ◽  
Hek293 Cells ◽  
Caspase 8 ◽  
Cytotoxic Effects ◽  
Protein Protein Interaction ◽  
Rich Domain

ABSTRACT Apoptosis repressor with CARD (ARC) possesses the ability not only to block activation of caspase 8 but to modulate caspase-independent mitochondrial events associated with cell death. However, it is not known how ARC modulates both caspase-dependent and caspase-independent cell death. Here, we report that ARC is a Ca2+-dependent regulator of caspase 8 and cell death. We found that in Ca2+ overlay and Stains-all assays, ARC protein bound to Ca2+ through the C-terminal proline/glutamate-rich (P/E-rich) domain. ARC expression reduced not only cytosolic Ca2+ transients but also cytotoxic effects of thapsigargin, A23187, and ionomycin, for which the Ca2+-binding domain of ARC was indispensable. Conversely, direct interference of endogenous ARC synthesis by targeting ARC enhanced such Ca2+-mediated cell death. In addition, binding and immunoprecipitation analyses revealed that the protein-protein interaction between ARC and caspase 8 was decreased by the increase of Ca2+ concentration in vitro and by the treatment of HEK293 cells with thapsigargin in vivo. Caspase 8 activation was also required for the thapsigargin-induced cell death and suppressed by the ectopic expression of ARC. These results suggest that calcium binding mediates regulation of caspase 8 and cell death by ARC.

scholarly journals CISD3 inhibition drives cystine-deprivation induced ferroptosis

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Yanchun Li ◽  
Xin Wang ◽  
Zhihui Huang ◽  
Yi Zhou ◽  
Jun Xia ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Pathological Process ◽  
Metabolic Reprogramming ◽  
Regulatory Role ◽  
Underlying Mechanisms

AbstractFerroptosis, a new form of programmed cell death, not only promotes the pathological process of various human diseases, but also regulates cancer progression. Current perspectives on the underlying mechanisms remain largely unknown. Herein, we report a member of the NEET protein family, CISD3, exerts a regulatory role in cancer progression and ferroptosis both in vivo and in vitro. Pan-cancer analysis from TCGA reveals that expression of CISD3 is generally elevated in various human cancers which are consequently associated with a higher hazard ratio and poorer overall survival. Moreover, knockdown of CISD3 significantly accelerates lipid peroxidation and accentuates free iron accumulation triggered by Xc– inhibition or cystine-deprivation, thus causing ferroptotic cell death. Conversely, ectopic expression of the shRNA-resistant form of CISD3 (CISD3res) efficiently ameliorates the ferroptotic cell death. Mechanistically, CISD3 depletion presents a metabolic reprogramming toward glutaminolysis, which is required for the fuel of mitochondrial oxidative phosphorylation. Both the inhibitors of glutaminolysis and the ETC process were capable of blocking the lipid peroxidation and ferroptotic cell death in the shCISD3 cells. Besides, genetic and pharmacological activation of mitophagy can rescue the CISD3 knockdown-induced ferroptosis by eliminating the damaged mitochondria. Noteworthily, GPX4 acts downstream of CISD3 mediated ferroptosis, which fails to reverse the homeostasis of mitochondria. Collectively, the present work provides novel insights into the regulatory role of CISD3 in ferroptotic cell death and presents a potential target for advanced antitumor activity through ferroptosis.

Optimization and efficacy study of synergistic vincristine coloaded liposomal doxorubicin against breast and lung cancer

Nanomedicine ◽  
2020 ◽  
Vol 15 (26) ◽  
pp. 2585-2607
Author(s):  
Saikat Ghosh ◽  
Rohan Lalani ◽  
Kuntal Maiti ◽  
Shubhadeep Banerjee ◽  
Vivek Patel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Liposomal Doxorubicin ◽  
Triple Negative ◽  
Tumor Regression ◽  
Evaluation Studies ◽  
Poly Ethylene Glycol ◽  
Efficacy Evaluation ◽  
Poly Ethylene

Aim: To improve the efficacy of poly-ethylene glycol (PEG)ylated liposomes coloaded with doxorubicin and vincristine against triple-negative breast cancer (TNBC) and non-small-cell lung cancer (NSCLC). Methods: The combinatorial index of the drugs was established using the Chou-Talalay method in MDA-MB-231 and A549 cell lines. The most effective ratio was co-encapsulated in factorial design optimized nanoliposomes which were characterized for similarity to clinical standard and evaluated in vitro and in vivo for therapeutic efficacy. Results & conclusion: The formulation exhibited more than 95% co-encapsulation, a size of 95.74 ± 2.65 nm and zeta potential of -9.17 ± 1.19 mV while having no significant differences in physicochemical and biochemical characteristics as compared with the clinical standard. Efficacy evaluation studies showed significantly improved cytotoxicity and tumor regression compared with liposomal doxorubicin indicating improvement in efficacy against TNBC and NSCLC.

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