Anticancer bioactive peptides suppress human colorectal tumor cell growth and induce apoptosis via modulating the PARP-p53-Mcl-1 signaling pathway

Su, Liya; Shi, Yue; Yan, Mingxia; Xi, Yaguang; Su, Xiulan

doi:10.1038/aps.2015.80

Cited by 34 publications

(15 citation statements)

References 17 publications

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“…Nevertheless, it seems encouraging that the combination of CDK inhibitors with other chemotherapeutic drugs will enhance the efficacy and reduce unfavorable toxicity of CDK inhibitors, which has been confirmed in many preclinical and clinical settings aimed at lowering the cancer burden [37,38] . On the other side, the over-expression of the anti-apoptotic Bcl-2 family proteins Bcl-2, Bcl-xL, and Mcl-1 is frequently associated with acute leukemia progression and resistance to conventional chemotherapies [39][40][41] . Bcl-2 and Mcl-1 usually compensate each other's function in tumor cells [42] .…”

Section: Discussionmentioning

confidence: 99%

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

et al. 2016

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Aim: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. Methods: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA. The expression of relevant signaling molecules was assessed using Western blotting and RT-PCR. Primary lymphocytes from patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were separated using Ficoll-Paque PLUS. Results: LS-007 inhibited the proliferation of 6 AL cell lines with IC 50 values of 100-200 nmol/L, and decreased the survival of ALL and AML patient-derived lymphocytes with mean LD 50 value of 67 and 102 nmol/L, respectively. In kinase assays in vitro, LS-007 was more selective for the CDK family, inhibiting CDK2, CDK9, CDK1 and CDK4 at low nanomolar concentrations. In HL-60 and CCRF-CEM cells, LS-007 (0.1-0.4 μmol/L) dose-dependently induced cell apoptosis predominantly through CDK9 inhibition-related dephosphorylation at the ser2 residue of RNA pol II and the corresponding depletion of anti-apoptotic proteins, especially Mcl-1 and XIAP. LS-007 (0.2 and 0.4 μmol/L) also induced cell apoptosis in the patient-derived lymphocytes. In HL-60, CCRF-CEM and Molt-4 cells, combined application of LS-007 with ABT-199 (1 or 2 μmol/L) markedly increased cell apoptosis with a maximal decrease in the XIAP levels as compared with either drug used alone. Conclusion: CDK inhibitor LS-007 potently inhibits the established human AL cell lines and primary AL blasts, and it also shows remarkable synergy with Bcl-2 inhibitor

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Section: Discussionmentioning

confidence: 99%

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

et al. 2016

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“…In vivo, ACBP-3 alone or in combination with cisplatin suppresses xenograft tumor growth, and this peptide enhances the chemotherapy tolerance of mice by reducing the toxicity of the treatment during long-term experiments (15,16). The Su group also investigated the anticancer activity of ACBPs in a human colorectal tumor cell line (HCT116) in vitro and in vivo (17). Specifically, treatment with ACBPs significantly inhibits HCT116 cell growth, enhances Uv-induced apoptosis, increases the expression levels of PARP and p53, and decreases the expression of Mcl-1.…”

Section: Animal Sources Of Bioactive Peptides With Anticancer Activitymentioning

confidence: 99%

Anticancer potential of bioactive peptides from animal sources

et al. 2017

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Cancer is the most common cause of human death worldwide. Conventional anticancer therapies, including chemotherapy and radiation, are associated with severe side effects and toxicities as well as low specificity. Peptides are rapidly being developed as potential anticancer agents that specifically target cancer cells and are less toxic to normal tissues, thus making them a better alternative for the prevention and management of cancer. Recent research has focused on anticancer peptides from natural animal sources, such as terrestrial mammals, marine animals, amphibians, and animal venoms. However, the mode of action by which bioactive peptides inhibit the proliferation of cancer cells remains unclear. In this review, we present the animal sources from which bioactive peptides with anticancer activity are derived and discuss multiple proposed mechanisms by which these peptides exert cytotoxic effects against cancer cells.

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“…Tumor suppressor p53 is a key transcription factor, which activates or represses varieties of genes expression and has been documented in multiple biological processes [1][2][3]. It plays an important role in apoptosis, cell cycle arrest, metabolism, senescence and is a crucial regulator of therapeutic targets in cancer [4][5][6]. The expression of p53 is subject to a large number of regulations at the levels of transcription, posttranscription and translation [7].…”

Section: Introductionmentioning

confidence: 99%

The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways

Wang

Jiang

et al. 2018

Acta Pharmacol Sin

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Mammalian hepatitis B X-interacting protein (HBXIP) is an 18-kDa protein that regulates a large number of transcription factors such as TF-IID, E2F1, SP1, STAT3, c-Myc, and LXR by serving as an oncogenic transcription coactivator and plays an important role in the development of breast cancer. We previously showed that HBXIP as an oncoprotein could enhance the promoter activity of MDM2 through coactivating p53, promoting the MDM2 transcription in breast cancer. In this study we investigated the molecular mechanisms underlying the modulation of MDM2/p53 interaction by HBXIP in human breast cancer MCF-7 cells in vitro and in vivo. We showed that HBXIP could up-regulate MDM2 through inducing DNA methylation of miR-18b, thus suppressing the miR-18b expression, leading to the attenuation of p53 in breast cancer cells. In addition, HBXIP could promote the phosphorylation of MDM2 by increasing the level of pAKT and bind to pMDM2, subsequently enhancing the interaction between MDM2 and p53 for the down-regulation of p53 in breast cancer cells. In MCF-7 breast cancer xenograft nude mice, we also observed that overexpression of HBXIP promoted breast cancer growth through the miR-18b/MDM2 and pAKT/MDM2 pathways. In conclusion, oncoprotein HBXIP suppresses miR-18b to elevate MDM2 and activates pAKT to phosphorylate MDM2 for enhancing the interaction between MDM2 and p53, leading to p53 degradation in promotion of breast cancer growth. Our findings shed light on a novel mechanism of p53 down-regulation during the development of breast cancer.

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Anticancer bioactive peptides suppress human colorectal tumor cell growth and induce apoptosis via modulating the PARP-p53-Mcl-1 signaling pathway

Cited by 34 publications

References 17 publications

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Anticancer potential of bioactive peptides from animal sources

The oncoprotein HBXIP promotes human breast cancer growth through down-regulating p53 via miR-18b/MDM2 and pAKT/MDM2 pathways

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