Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival

Nam, Jehyun; Kim, Dong Uk; Kim, Eungyoung; Kwak, Bomi; Ko, Minji; Oh, Ah Young; Park, Bum-Joon; Kim, Yea Woon; Kim, AeRi; Sun, Hokeun; Jung, Youngmi; Lee, Jae‐Hoon; Shin, Ho-Jin; Park, Inmyoung; Song, Dae‐Kyu; Jeong, Jee‐Yeong; Lee, Yun‐Han; Kim, Sang Woo

doi:10.1038/s41375-019-0492-y

Cited by 12 publications

(20 citation statements)

References 47 publications

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“…55 ), as well as that of additional downstream c-MYC targets (PDE3B and ODC1) (Fig. 6k) 56 . These effects were observed with no decrease in PIN1 protein abundance, suggesting that CL71 can inhibit PIN1 catalytic activity (Supplementary Fig.…”

Section: Specific Protein Target Engagement and Sarmentioning

confidence: 87%

Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries

et al. 2021

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Current methods used for measuring amino acid side-chain reactivity lack the throughput needed to screen large chemical libraries for interactions across the proteome. Here we redesigned the workflow for activity-based protein profiling of reactive cysteine residues by using a smaller desthiobiotin-based probe, sample multiplexing, reduced protein starting amounts and software to boost data acquisition in real time on the mass spectrometer. Our method, streamlined cysteine activity-based protein profiling (SLC-ABPP), achieved a 42-fold improvement in sample throughput, corresponding to profiling library members at a depth of >8,000 reactive cysteine sites at 18 min per compound. We applied it to identify proteome-wide targets of covalent inhibitors to mutant Kirsten rat sarcoma (KRAS) G12C and Bruton's tyrosine kinase (BTK). In addition, we Reprints and permissions information is available at www.nature.com/reprints.

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Section: Specific Protein Target Engagement and Sarmentioning

confidence: 87%

Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries

et al. 2021

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“…Scale bar, 1 (c) Mouse body weights were measured every 2 days for 10 days during the treatment. (Ly1 CDH) that were well-characterized in previous studies [22]. We presumed that Myc overexpression would render the cells resistant to continentalic acid if Myc was involved in this process.…”

Section: Continentalic Acid Induces Apoptosis Depending On Caspase and Mitochondria By Regulating Bcel-2 Family Membersmentioning

confidence: 92%

“…In addition, this oncogene has been shown to play a critical role in the survival and aggressiveness of hematological cancers. To directly test whether continentalic acidinduced cell death is associated with regulation of Myc, we used Ly1 cells ectopically expressing Myc (Ly1 CDH-Myc) and control cells transduced with a control lentiviral vec-tor (Ly1 CDH) that were well-characterized in previous studies [22]. We presumed that Myc overexpression would render the cells resistant to continentalic acid if Myc was involved in this process.…”

Section: Continentalic Acid Induces Apoptosis Depending On Caspase and Mitochondria By Regulating Bcel-2 Family Membersmentioning

confidence: 99%

“…To measure cell viability, the CellTiter 96 AQueous One Solution [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] cell proliferation assays (MTSs) were conducted according to the manufacturer's instructions (Promega, Madison, WI, USA) after treatment with ACE-H, ACE-S1, ACE-W252, epi-continentalic acid, continentalic acid, and kaurenoic acid alone or in combination with roflumilast as indicated [22]. Briefly, 3 × 10 4 cells per well of 96-well plates were seeded in RPMI1640 with 10% FBS, and the cells were treated for 24 h as indicated, followed by measurement of cell viability by MTS assays.…”

Section: Cell Viability and Apoptosis Assaysmentioning

confidence: 99%

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Anticancer Activity of Continentalic Acid in B-Cell Lymphoma

et al. 2021

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Aralia continentalis has been used in Korea as a folk remedy for arthralgia, rheumatism, and inflammation. However, its anti-lymphoma effect remains uncharacterized. Here, we demonstrate that A. continentalis extract and its three diterpenes efficiently kill B-lymphoma cells. Our in vitro and in vivo results suggest that the cytotoxic activities of continentalic acid, a major diterpene from A. continentalis extract, are specific towards cancer cells while leaving normal murine cells and tissues unharmed. Mechanistically, continentalic acid represses the expression of pro-survival Bcl-2 family members, such as Mcl-1 and Bcl-xL. It dissociates the mitochondrial membrane potential, leading to the stimulation of effector caspase 3/7 activities and, ultimately, cell death. Intriguingly, this agent therapeutically synergizes with roflumilast, a pan-PDE4 inhibitor that has been successfully repurposed for the treatment of aggressive B-cell malignancies in recent clinical tests. Our findings unveiled that A. continentalis extract and three of the plant’s diterpenes exhibit anti-cancer activities. We also demonstrate the synergistic inhibitory effect of continentalic acid on the survival of B-lymphoma cells when combined with roflumilast. Taken in conjunction, continentalic acid may hold significant potential for the treatment of B-cell lymphoma.

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“…Hematoxylin and eosin (H&E) staining. H&E staining was performed as previously described (14,15). After sacrificing the mice, the lung, heart, liver and one kidney per mouse were isolated, and the specimens were fixed with 10% neutral buffered formalin solution (Sigma-Aldrich; Merck KGaA) at 4˚C overnight.…”

Section: High-performance Liquid Chromatography (Hplc) Analysismentioning

confidence: 99%

Dracocephalum palmatum Stephan extract induces caspase‑ and mitochondria‑dependent apoptosis via Myc inhibition in diffuse large B cell lymphoma

Kim

Park

et al. 2020

Oncol Rep

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Dracocephalum palmatum Stephan (DPS), a medicinal plant used by Russian nomads, has been known to exhibit antioxidant properties. However, to the best of our knowledge, its anticancer effect has not been elucidated. The present study aimed to evaluate the tumor-suppressive effect of DPS extract (DPSE) in diffuse large B cell lymphoma (DLBCL) and the underlying mechanism. MTS assays and Annexin V staining were performed to assess the anti-proliferative and apoptotic effects of DPSE, respectively. To reveal the underlying mechanisms, the levels of pro-and anti-apoptotic Bcl-2 members were analyzed by western blotting. Rescue experiments were performed to investigate the potential involvement of Myc in DPSE-induced tumor-inhibitory effects. Additionally, high-performance liquid chromatography analysis was performed to analyze the components with anticancer effects. Exposure of multiple DLBCL cell lines to DPSE significantly decreased cell viability and increased apoptosis, whereas it had no effect on the survival of normal cells in vitro and in vivo. This indicates that its cytotoxic effect may be specific to cancer cells. Mechanistically, cell death induced by DPSE was dependent on the activation of caspase-3/7 and the disruption of mitochondrial membrane potential. Treatment with the extract ameliorated the expression of anti-apoptotic Bcl-2 members Bcl-xL and Mcl-1, and upregulated that of pro-apoptotic Bcl-2 members Bax and Bak. These modulations led to the disruption of mitochondrial membrane potential, which culminated in the activation of executioner caspases-3 and -7. Notably, overexpression of Myc inhibited DPSE-induced cell killing, indicating the involvement of Myc in this process. Given that dysregulation of Myc is strongly associated with the pathobiology of DLBCL, the present study highlights the potential therapeutic efficacy of DPSE in patients with DLBCL with aberrant Myc expression. Furthermore, fractionation of DPSE by thin layer chromatography and liquid chromatography/mass spectrometry-based investigation of the fraction with bioactive compounds demonstrated that flavonoids may be responsible for most, if not all, of the anti-lymphoma effect. Efforts to identify the bioactive flavonoids is currently underway.

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Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival

Cited by 12 publications

References 47 publications

Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries

Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries

Anticancer Activity of Continentalic Acid in B-Cell Lymphoma

Dracocephalum palmatum Stephan extract induces caspase‑ and mitochondria‑dependent apoptosis via Myc inhibition in diffuse large B cell lymphoma

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