Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis

Erkes, Dan A.; Cai, Weijia; Sanchez, Ileine M.; Purwin, Timothy J.; Rogers, Corey; Field, Conroy O.; Berger, Adam C.; Hartsough, Edward J.; Rodeck, Ulrich; Alnemri, Emad S.; Aplin, Andrew E.

doi:10.1158/2159-8290.cd-19-0672

Cited by 338 publications

(346 citation statements)

References 64 publications

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“…As a critical form of cell death, pyroptosis has been reported to be involved in many physiological processes, such as regulation of tumor immune microenvironment [35], treatment of acute myeloid leukemia [36] and act as an innate immune effector against intracellular bacteria [37]. There are various researches showing an association between pyroptosis and tumor proliferation [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway

2020

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Cervical cancer is the fourth most common cancer in women globally. Lack of effective pharmacotherapies for cervical cancer mainly attributed to an elusive understanding of the mechanism underlying its pathogenesis. Pyroptosis plays a key role in inflammation and cancer. Our study identified microRNA (miR) 145 (miR-145)/gasdermin D (GSDMD) signaling pathway as critical mediators in the effect of tanshinone II A on HeLa cells. In the present study, we found that treatment of tanshinone II A led to an obvious repression of cell proliferation and an increase in apoptosis on HeLa cells, especially in high concentration. Compared with the controlled group, tanshinone II A enhanced the activity of caspase3 and caspase9. Notably, the results demonstrated that tanshinone II A regulated cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway. Treatment of tanshinone II A significantly up-regulated the expression of GSDMD and miR-145. After transfection of si-miR-145 plasmids, the effects of tanshinone II A on HeLa cells were converted, including cell proliferation, apoptosis and pyroptosis. In addition, the results showed that tanshinone II A treatment altered the expression level of PI3K, p-Akt, NF-kB p65 and Lc3-I. Collectively, our findings demonstrate that tanshinone II A exerts anticancer activity on HeLa cells by regulating miR-145/GSDMD signaling. The present study is the first time to identify miR-145 as a candidate target in cervical cancer and show an association between miR-145 and pyroptosis, which provides a novel therapy for the treatment of cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway

2020

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“…Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are Food and Drug Administration (FDA)-approved to treat BRAF V600E/K mutant melanoma. BRAFi + MEKi treatment promotes cleavage of GSDME and release of high-mobility group protein B1 (HMGB1) to induce cell pyroptotic death [91]. Transcription factor p53 overexpression triggers pyroptosis to suppress tumor growth in A549 tumor-bearing mice.…”

Section: Non-chemotherapy Drug-induced Pyroptosis Exerts Anticancer Ementioning

confidence: 99%

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

Zheng

2020

IJMS

146

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Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy.

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“…Mechanistically, gasdermin E was indispensable for melanoma cell response as GSDME deficiency resulted in more frequent tumor re-growth when administration of drugs was ceased. Notably, BRAFi-and MEKi-resistant cells were still sensitive to pyroptosis-inducing compounds [222].…”

Section: Pyroptosis In Melanomamentioning

confidence: 99%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

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Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis

Cited by 338 publications

References 64 publications

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

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