Derivatives of 6-cinnamamido-quinoline-4-carboxamide impair lysosome function and induce apoptosis

Kuo, Hsiao-Hui; Kakadiya, Rajesh; Wu, Yichen; Su, Te‐Jen; Lee, Te‐Chang; Lin, Yi‐Wen; Yih, Ling-Huei

doi:10.18632/oncotarget.9348

Cited by 16 publications

(10 citation statements)

References 49 publications

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“…However, the exact effect of MAPK/ERK on autophagy activation and maturation has not been de ned and generates controversial results [35]. Increasing evidence demonstrates that prolonged activation of MAPK/ERK induced by drug treatment has been indicated to block the maturation process of autophagy [36,37]. In consistent with these studies, our results indicated that both autophagy and ERK were activated while autophagic ux was impaired after treatment with T-96.…”

Section: Discussionsupporting

confidence: 82%

“…5B). Accumulating evidence also indicated that drugmediated activation of MAPK/ERK can impair autophagy maturation by disrupting the fusion between autophagosome and lysosome [36,37].To further determine whether T-96 is capable to modulate the progression of autophagic ux, double tagged mCherry-GFP-LC3B reporter, which is pH sensitive, was transfected into CaP cells to evaluate the fusion e ciency of autophagosome and lysosome. The yellow uorescent represented the number of non-acidic autophagosomes, whereas the red uorescent labeled autolysosomes.…”

Section: T-96 Initiated Autophagy While Blocked Autophagic Ux and Subsequently Induced Apoptosismentioning

confidence: 99%

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Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

Yang

Zhang

et al. 2021

Preprint

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Demethylzeylasteral (T-96), a pharmacologically active triterpenoid monomer extracted from Tripterygiumwilfordii Hook F (TWHF), has been reported to exhibit anti-neoplastic effect on several types of cancer cells. However,whether it has the anti-tumour capability in human Prostate cancer (CaP)cells and what’s the precise regulatory mechanisms underlying the anti-proliferation effect of T-96 on human CaP. In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Furthermore, mechanistic investigation indicated that through inducing endoplasmic reticulum (ER) stress caused by intracellular accumulation of reactive oxygen species (ROS), T-96 significantly promoted autophagy initiation while blocked the autophagic flux and finally caused extrinsic apoptosis in CaP cells, implying that ER stress induced byT-96 initiated caspase dependent apoptosis to inhibit CaP cells. Moreover, as a novel lethal ER stress inducer, T-96 was capable to enhance the sensitivity of CaP cells to chemotherapeutic drug cisplatin. Taken together, our data implied that T-96 is a novel ER stress and autophagy modulator, and has the potential applications for CaP therapy in clinic.

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Section: Discussionsupporting

confidence: 82%

Section: T-96 Initiated Autophagy While Blocked Autophagic Ux and Subsequently Induced Apoptosismentioning

confidence: 99%

Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

Yang

Zhang

et al. 2021

Preprint

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“…However, the precise role of MAPK/ERK in autophagy initiation or maturation has not been defined and yields controversial results 28 . Accumulating evidence indicates that impaired autophagy through disruption of lysosomal function can be triggered by druginduced activation of MAPK/ERK and thus increases cell death 68,69 . Sustained activation of MAPK/ERK has been shown to inhibit the maturation step of the autophagy process 68 .…”

Section: Discussionmentioning

confidence: 99%

Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation

et al. 2019

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Targeting autophagy may serve as a promising strategy for cancer therapy. Ganoderma lucidum polysaccharide (GLP) has been shown to exert promising anti-cancer effects. However, the underlying mechanisms remain elusive. Whether GLP regulates autophagy in cancer has never been reported. In this study, GLP induced the initiation of autophagy in colorectal cancer (CRC) HT-29 and HCT116 cells, as evidenced by enhanced level of LC3-II protein, GFP-LC3 puncta, and increased formation of double membrane vacuoles. However, GLP treatment caused marked increase of p62 expression. Addition of late stage autophagy inhibitor, chloroquine (CQ), further enhanced LC3-II and p62 level, as well as increased autophagosome accumulation, suggesting a blockage of autophagic flux by GLP in CRC cells. We then found GLP blocked autophagosome and lysosome fusion as determined by mRFP-GFP-LC3 colocalization analysis. Mechanistic study revealed that GLP-induced disruption of autophagosome-lysosome fusion is due to reduced lysosome acidification and lysosomal cathepsin activities. Cell viability and flow cytometry assays revealed that GLPinduced autophagosome accumulation is responsible for GLP-induced apoptosis in CRC cells. In line with this, inhibition of autophagy initiation by 3-methyladenine (3-MA), an early stage autophagy inhibitor, attenuated GLPinduced apoptosis. In contrast, suppression of autophagy at late stage by CQ enhanced the anti-cancer effect of GLP. Furthermore, we demonstrated that GLP-induced autophagosome accumulation and apoptosis is mediated via MAPK/ERK activation. Finally, GLP inhibited tumor growth and also inhibited autophagic flux in vivo. These results unveil new molecular mechanism underlying anti-cancer effects of GLP, suggesting that GLP is a potent autophagy inhibitor and might be useful in anticancer therapy.

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“…ERK-dependent autophagic activity is related to specific autophagy markers, such as LC3B-II, beclin1, BNIP-3 and G-interacting protein (GAIP) ( Ogier-Denis et al, 2000 ; An et al, 2006 ; Cheng et al, 2008 ; Tong et al, 2015 ). In addition, accelerating evidence suggests that activation of MEK1/2-ERK1/2 cascade impairs autophagy by disruption of lysosomal function ( Corcelle et al, 2006 ; Kuo et al, 2016 ). Our study found TBMS1-induced autophagy initiation in melanoma cells by MEK1/2-ERK1/2 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Tubeimoside I Inhibits Cell Proliferation and Induces a Partly Disrupted and Cytoprotective Autophagy Through Rapidly Hyperactivation of MEK1/2-ERK1/2 Cascade via Promoting PTP1B in Melanoma

Dong

Tan

et al. 2020

Front. Cell Dev. Biol.

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Tubeimoside I (TBMS1), also referred to as tubeimoside A, is a natural compound extracted from the plant Tu Bei Mu (Bolbostemma paniculatum), which is a traditional Chinese herb used to treat multiple diseases for more than 1,000 years. Studies in recent years reported its anti-tumor activity in several cancers. However, whether it is effective in melanoma remains unknown. In the current study, we discovered that TBMS1 treatment inhibited melanoma cell proliferation in vitro and tumorigenecity in vivo. Besides, we also observed that TBMS1 treatment induced a partly disrupted autophagy, which still remained a protective role, disruption of which by chloroquine (CQ) or 3-methyladenine (3-MA) enhanced TBMS1-induced cell proliferation inhibition. CQ combined with TBMS1 even induced cellular apoptosis. BRAF(V600E) mutation and its continuously activated downstream MEK1/2-ERK1/2 cascade are found in 50% of melanomas and are important for malanomagenesis. However, hyperactivating MEK1/2-ERK1/2 cascade can also inhibit tumor growth. Intriguingly, we observed that TBMS1 rapidly hyperactivated MEK1/2-ERK1/2, inhibition of which by its inhibitor SL-327 rescued the anti-cancerous effects of TBMS1. Besides, the targets of TBMS1 were predicted by the ZINC Database based on its structure. It is revealed that protein-tyrosine phosphatase 1B (PTP1B) might be one of the targets of TBMS1. Inhibition of PTP1B by its selective inhibitor TCS401 or shRNA rescued the anti-cancerous effects of TBMS1 in melanoma cells. These results indicated that TBMS1 might activate PTP1B, which further hyperactivates MEK1/2-ERK1/2 cascade, thereby inhibiting cell proliferation in melanoma. Our results provided the potentiality of TBMS1 as a drug candidate for melanoma therapy and confirmed that rapidly hyperactivating an oncogenic signaling pathway may also be a promising strategy for cancer treatment.

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Derivatives of 6-cinnamamido-quinoline-4-carboxamide impair lysosome function and induce apoptosis

Cited by 16 publications

References 49 publications

Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation

Tubeimoside I Inhibits Cell Proliferation and Induces a Partly Disrupted and Cytoprotective Autophagy Through Rapidly Hyperactivation of MEK1/2-ERK1/2 Cascade via Promoting PTP1B in Melanoma

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