Par-4 activation restrains EMT-induced chemoresistance in PDAC by attenuating MDM-2

Ahmad, Syed Mudabir; Nayak, Debasis; Mir, Khalid Bashir; Faheem, Mir Mohd; Nawaz, Shah; Yadav, Govind; Goswami, Anindya

doi:10.1016/j.pan.2020.09.021

Cited by 18 publications

(7 citation statements)

References 39 publications

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“…Western blotting was performed as described previously ( 30 ). Following the respective treatments and transfections (see figure legends), cell lysates were prepared with lysis buffer containing protease and phosphatase inhibitors.…”

Section: Methodsmentioning

confidence: 99%

β-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPβ mediates the transition of breast cancer cells from autophagy to senescence

et al. 2022

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ATF-4 is a master regulator of transcription of genes essential for cellular-adaptive function. In response to the quantum and duration of stress, ATF-4 diligently responds to both pro-apoptotic and pro-survival signals converging into either autophagy or apoptosis/senescence. Despite emerging cues implying a relationship between autophagy and senescence, how these two processes are controlled remains unknown. Herein, we demonstrate β-(4-fluorobenzyl) Arteannuin B (here after Arteannuin 09), a novel semisynthetic derivative of Arteannuin B, as a potent ER stress inducer leading to the consistent activation of ATF-4. Persistent ATF-4 expression at early time-points facilitates the autophagy program and consequently by upregulating p21 at later time-points, the signaling is shifted towards G2/M cell cycle arrest. As bZIP transcription factors including ATF-4 are obligate dimers, and because ATF-4 homodimers are not highly stable, we hypothesized that ATF-4 may induce p21 expression by physically interacting with another bZIP family member i.e., C/EBPβ. Our co-immunoprecipitation and co-localization studies demonstrated that ATF-4 is principally responsible for the autophagic potential of Arteannuin 09, while as, induction of both ATF-4 and C/EBPβ is indispensable for the p21 regulated-cell cycle arrest. Interestingly, inhibition of autophagy signaling switches the fate of Arteannuin 09 treated cells from senescence to apoptosis. Lastly, our data accomplished that Arteannuin 09 is a potent inhibitor of tumor growth and inducer of premature senescence in vivo.

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Section: Methodsmentioning

confidence: 99%

β-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPβ mediates the transition of breast cancer cells from autophagy to senescence

et al. 2022

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“…Therefore, if some factors suppress EMT, sensitivity of tumor cells to chemotherapy enhances. Upregulation of Par-4 decreases MDM-2 expression to suppress EMT-mediated drug resistance [ 146 ]. Moreover, miR-128-3p-mediated suppression of c-Met/EMT axis leads to increased temozolomide sensitivity in glioblastoma [ 147 ].…”

Section: Wnt/β-catenin Signaling and Cancer Drug Resistance Via Regul...mentioning

confidence: 99%

Wnt/β-catenin-driven EMT regulation in human cancers

Xue,

Yang,

Chen

et al. 2024

Cell. Mol. Life Sci.

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Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation of epithelial cells into mesenchymal cells with molecular alterations can occur during epithelial–mesenchymal transition (EMT). The EMT mechanism accelerates the cancer metastasis and drug resistance ability in human cancers. Among the different regulators of EMT, Wnt/β-catenin axis has been emerged as a versatile modulator. Wnt is in active form in physiological condition due to the function of GSK-3β that destructs β-catenin, while ligand–receptor interaction impairs GSK-3β function to increase β-catenin stability and promote its nuclear transfer. Regarding the oncogenic function of Wnt/β-catenin, its upregulation occurs in human cancers and it can accelerate EMT-mediated metastasis and drug resistance. The stimulation of Wnt by binding Wnt ligands into Frizzled receptors can enhance β-catenin accumulation in cytoplasm that stimulates EMT and related genes upon nuclear translocation. Wnt/β-catenin/EMT axis has been implicated in augmenting metastasis of both solid and hematological tumors. The Wnt/EMT-mediated cancer metastasis promotes the malignant behavior of tumor cells, causing therapy resistance. The Wnt/β-catenin/EMT axis can be modulated by upstream mediators in which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT axis in metastasis suppression. Graphical abstract

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“…A correlation between MDM2 and the EMT has been reported in many cancer types, including lung cancer ( Tang et al, 2019 ), ovarian cancer ( Chen et al, 2017b ), and breast cancer ( Hauck et al, 2017 ). Gemcitabine treatment can enhance the expression of MDM2 and increase mesenchymal properties in pancreatic and breast cancer ( Ahmad et al, 2020 ). Recent studies have demonstrated that MDM2 promotes the EMT via MDM2/p53/14-3-3 signaling mediated by v-raf murine sarcoma viral oncogene homolog B1 (B-raf) activity ( Ou et al, 2021 ).…”

Section: The Rationale For Targeting Mdm2 For Molecular Targeted Therapymentioning

confidence: 99%

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Wang,

Albadari,

et al. 2024

Pharmacol Rev

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Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. Significance Statement Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.

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Par-4 activation restrains EMT-induced chemoresistance in PDAC by attenuating MDM-2

Cited by 18 publications

References 39 publications

β-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPβ mediates the transition of breast cancer cells from autophagy to senescence

β-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPβ mediates the transition of breast cancer cells from autophagy to senescence

Wnt/β-catenin-driven EMT regulation in human cancers

MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

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