Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells

Hsin, I.; Wang, Shao-Chuan; Li, Jian-Ri; Ciou, Tsai-Chun; Wu, Chen; Wu, Hung‐Ming; Ko, Jiunn‐Liang

doi:10.1016/j.phymed.2016.09.003

Cited by 29 publications

(16 citation statements)

References 43 publications

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“…Chloroquine has been reported to synergize with chemotherapy in numerous cancer types. With few exceptions, the primary underlying mechanism of synergism described was autophagy inhibition [ 28 , 30 , 32 , 33 ]. In contrast, Seitz et al described how chloroquine triggered apoptosis in concert with PI3 kinase inhibition in neuroblastoma cells, in an LMP-mediated fashion [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells

Circu

Cardelli²,

Barr

et al. 2017

PLoS ONE

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Lung cancer is the leading cause of cancer-related deaths. Most patients develop resistance to platinum within several months of treatment. We investigated whether triggering lysosomal membrane permeabilization (LMP) or suppressing autophagy can restore cisplatin susceptibility in lung cancer with acquired chemoresistance. Cisplatin IC50 in A549Pt (parental) and A549cisR (cisplatin resistant) cells was 13 μM and 47 μM, respectively. Following cisplatin exposure, A549cisR cells failed to elicit an apoptotic response. This was manifested by diminished Annexin–V staining, caspase 3 and 9, BAX and BAK activation in resistant but not in parental cells. Chloroquine preferentially promoted LMP in A549cisR cells, revealed by leakage of FITC-dextran into the cytosol as detected by immunofluorescence microscopy. This was confirmed by increased cytosolic cathepsin D signal on Immunoblot. Cell viability of cisplatin-treated A549cisR cells was decreased when co-treated with chloroquine, corresponding to a combination index below 0.8, suggesting synergism between the two drugs. Notably, chloroquine activated the mitochondrial cell death pathway as indicated by increase in caspase 9 activity. Interestingly, inhibition of lysosomal proteases using E64 conferred cytoprotection against cisplatin and chloroquine co-treatment, suggesting that chloroquine-induced cell death occurred in a cathepsin-mediated mechanism. Likewise, blockage of caspases partially rescued A549cisR cells against the cytotoxicity of cisplatin and chloroquine combination. Cisplatin promoted a dose-dependent autophagic flux induction preferentially in A549cisR cells, as evidenced by a surge in LC3-II/α-tubulin following pre-treatment with E64 and increase in p62 degradation. Compared to untreated cells, cisplatin induced an increase in cyto-ID-loaded autophagosomes in A549cisR cells that was further amplified by chloroquine, pointing toward autophagic flux activation by cisplatin. Interestingly, this effect was less pronounced in A549Pt cells. Blocking autophagy by ATG5 depletion using siRNA markedly enhances susceptibility to cisplatin in A549cisR cells. Taken together, our results underscore the utility of targeting lysosomal function in overcoming acquired cisplatin refractoriness in lung cancer.

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Section: Discussionmentioning

confidence: 99%

Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells

Circu

Cardelli²,

Barr

et al. 2017

PLoS ONE

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“…It has been established that caspase-8 or caspase-9 is activated by apoptosis stimulating factors, for example Cyt-C or the Fas Ligand-Fas-Fas-associated protein with death domain complex, which will trigger the downstream caspase-3, and the activated caspase-3 will directly cause the loss of DNA repair function and activation of endonuclease and DNA fragmentation, resulting in cell apoptosis (26,27). In the present study, it was observed that the A2780/DDP cells exposed to different concentrations of HNPG underwent apoptosis in a dose-dependent manner, accompanied by the upregulation of Cyt-C, cleaved caspase-9 and cleaved caspase-3.…”

Section: Discussionmentioning

confidence: 99%

Effects of 5‑hydroxy‑4'‑nitro‑7‑propionyloxy‑genistein on inhibiting proliferation and invasion via activating reactive oxygen species in human ovarian cancer A2780/DDP cells

2018

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Abstract. 5-hydroxy-4'-nitro-7-propionyloxy-genistein (HNPG), a novel synthetic isoflavone derivative, was demonstrated to possess antitumor activity in gastric cancer and breast cancer in vitro, but its antitumor effect and mechanism in ovarian cancer has not been characterized. The aim of the present study was to investigate the effects of HNPG on inhibiting the proliferation and invasion in human ovarian cancer A2780 cell lines of cisplatin resistance (A2780/DDP) and elucidate its underlying molecular mechanism. The results indicated that HNPG presented with marked antitumor activity against A2780/DDP cells in vitro, significantly inhibited the rates of proliferation, clone formation, invasion and metastasis, and markedly induced apoptosis in dose-and time-dependent manner. Simultaneously, levels of reactive oxygen species (ROS) were increased and mitochondrial membrane potential was decreased. In addition, Bcl-2 expression was downregulated, Bax expression was upregulated, and the ratio of Bcl-2/Bax was decreased. Concurrently, levels of Cyt-C were markedly enhanced and the caspase cascade was triggered. Taken together, the results suggested that HNPG exerted anticancer effects through promoting ROS accumulation in cells, triggering mitochondrial apoptotic pathways and ultimately resulting in cells apoptosis. Therefore, HNPG serves as a potential candidate in the chemoprevention and/or treatment of cisplatin-resistant human ovarian cancer.

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“…Lentiviral infection of H1355 cell line led to stable integration and expression of short hairpin RNA (shRNA) targeting the mRNA sequences of β‐catenin. The detailed steps of lentivirus production and infection have been described previously . Individual clones were identified by their unique TRC number: shLuc TRCN0000072246 for vector control targeted to luciferase, shβ‐catenin (#921) TRCN0000314921 (responding sequence: TCTAA CCTCA CTTGC AATAA T), and shβ‐catenin (#991) TRCN0000314991 (responding sequence: TTGTT ATCAG AGGAC TAAAT A) targeted to β‐catenin.…”

Section: Methodsmentioning

confidence: 99%

“…FIP‐gts, an immunomodulatory protein from Ganoderma tsugae , inhibits telomerase and induces premature senescence in lung cancer cells . FIP‐gts induces caspase‐independent cell death via triggering autophagy in cisplatin‐resistant urothelial cancer cells . GMI, a fungal immunomodulatory protein from Ganoderma microsporum , inhibits epidermal growth factor (EGF)‐induced metastasis and induces autophagic cell death in lung cancer cells .…”

Section: Introductionmentioning

confidence: 99%

GMI, an Immunomodulatory Protein from Ganoderma microsporum, Potentiates Cisplatin-Induced Apoptosis via Autophagy in Lung Cancer Cells

Hsin

et al. 2015

Mol. Pharmaceutics

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Cisplatin-based therapy is common in the treatment of several types of cancers, including lung cancers. In our previous study, GMI, an immunomodulatory protein cloned from Ganoderma microsporum, induced a cytotoxic effect in lung cancer cells via autophagy. The aim of this study is to examine the role of GMI in enhancing cisplatin-mediated cell death. On the basis of MTT assay and Combination Index, GMI and cisplatin cotreatment induced a synergistic cytotoxic effect. GMI and cisplatin-induced apoptosis was determined by sub-G1, nuclear condensation, and annexin-V/propidium iodide analyses. On Western blot, expressions of γH2AX and cleaved forms of PARP, caspase-3, and caspase-7 were induced by combined treatment. Akt/mTOR pathway activity, LC3-II expression, and acidic vesicular organelle development demonstrated that cisplatin does not abolish GMI-mediated autophagy. Cyto-ID Green/hoechst 33342 double staining and time-dependent experiment indicated that GMI and cisplatin-treated A549 cells simultaneously express autophagosomes and apoptotic nuclei. To elucidate the role of autophagy in inducing apoptosis by GMI and cisplatin, chemical inhibitors and LC3 shRNA were used to inhibit autophagy. The results showed that 3-methyladenine decreases, while chloroquine increases GMI and cisplatin cotreatment-induced cleavage of caspase-7 and PARP. LC3 silencing abolished activation of apoptosis in A549 cells. Caspase inhibitors and caspase-7 silencing mitigated GMI and cisplatin-elicited cell viability inhibition and apoptosis. This is the first study to reveal the novel function of GMI in potentiating cisplatin-mediated apoptosis. GMI and cisplatin induce apoptosis via autophagy/caspase-7-dependent and survivin- and ERCC1-independent pathway. GMI may be a potential cisplatin adjuvant against lung cancer.

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Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells

Cited by 29 publications

References 43 publications

Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells

Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells

Effects of 5‑hydroxy‑4'‑nitro‑7‑propionyloxy‑genistein on inhibiting proliferation and invasion via activating reactive oxygen species in human ovarian cancer A2780/DDP cells

GMI, an Immunomodulatory Protein from Ganoderma microsporum, Potentiates Cisplatin-Induced Apoptosis via Autophagy in Lung Cancer Cells

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