Involvement of HMGB1 in vemurafenib resistance in thyroid cancer cells harboring BRAF (V600E) mutation by regulating excessive autophagy

Lin, Run; Wang, Liping; Nong, Xiting; Li, Nan; Huang, Xin; Yang, Xiudong

doi:10.1007/s12020-020-02417-y

Cited by 11 publications

(7 citation statements)

References 29 publications

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“…Tomasz M et al reported miR-410-3p, which was induced by vemurafenib in melanoma cells via 10 ER stress, contributes to resistance to BRAF inhibitor [39]. In thyroid cancer, HMGB1-mediated autophagy may account for vemurafenib resistance [40]. Our team also demonstrated that targeting autophagy could sensitize BRAF-mutant thyroid cancer to vemurafenib [25].…”

Section: Discussionsupporting

confidence: 55%

BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma

Zhao

Wang

Zhang

et al. 2022

neo

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Melanoma with a BRAF mutation is more common to develop into a fatal disease. BRAF mutation inhibitor-induced autophagy affects the drug efficacy in many cancer types. The role of autophagy during BRAF inhibition in uveal melanoma (UM) remains unclear. In this study, we examined the autophagic flux and compared the number of autophagic vacuoles during the BRAF inhibition in UM. The PKR-like endoplasmic reticulum (ER) kinase (PERK) arm was studied to test whether the ER stress was involved. The effects of downregulation of ER stress by targeting the PERK arm (pharmacologically and genetically) were also assessed. We found a dose-dependent increase of autophagic flux in OCM1A cells during the BRAF inhibition. This phenomenon was further verified by an enhanced number of GFP-LC3 puncta and was finally confirmed by raised autophagic index examined by transmission electron microscopy. Pathway analysis revealed that the vemurafenib (the BRAF inhibitor)-induced autophagy was independent of the MAPK signaling pathway. Instead, it was possibly regulated via the enhanced ER stress response. We further found that the inhibition of ER stress response rescued cell death. Therefore, our results suggest BRAF inhibition promotes ER stress response-induced autophagy in UM. Targeting ER stress response can partially revert autophagy and rescue cell death, which may impair the anti-tumor effect of BRAF inhibitor in UM.

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Section: Discussionsupporting

confidence: 55%

BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma

Zhao

Wang

Zhang

et al. 2022

neo

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“…For example, vemurafenib (a BRAF inhibitor), sorafenib (a pan-tyrosine kinase inhibitor), apatinib (a VEGF-2 inhibitor) and cisplatin (a chemotherapeutic drug) suppress cell survival and proliferation, and simultaneously induce autophagy. Moreover, the anticancer effects of these agents can be augmented by autophagy inhibitors including chloroquine (CQ), 3-methyladenine (3-MA) and small interfering (si) RNA for ATG5 or BECLIN-1 [10][11][12][13][14][15][16], indicating the pro-survival effect of autophagy on thyroid cancer cells. In contrast, the anticancer effects of doxorubicin, apigenin and allicin, all of which are reported autophagy inducers, were inhibited by autophagy inhibition [17][18][19], suggesting the anti-survival effect of autophagy.…”

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confidence: 99%

Re-evaluation of the role of autophagy in thyroid cancer treatment

et al. 2022

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Numerous studies have examined the role of autophagy in thyroid cancer treatment; however there are discrepancies among the reported data, with some showing the pro-survival and others the anti-survival effects of autophagy. These discrepant results appear to be at least in part due to insufficient analyses or data misinterpretation as well as improper assessments of autophagic activity. Therefore, the present study re-evaluated the regulation of autophagic activity by various anticancer modalities and examined the role of autophagy in thyroid cancer treatment in three thyroid cancer cell lines (TPC1, ACT1 and KTC1). The immunofluorescence and DalGreen findings demonstrated that cisplatin, irradiation and sorafenib were all autophagy inducers as previously reported, but, unlike previous studies using thyroid cancer cells, doxorubicin acted as an inhibitor. KTC1 cells are unique because they only responded to cisplatin. The efficacy of anticancer therapeutics was significantly higher in chloroquine or 3-methyladenine-treated autophagy-defective cells than in autophagy-competent cells, thereby indicating the pro-survival effect of autophagy induced by anticancer therapeutics, which is partly due to inhibition of apoptosis. Thus, the present findings relating to several anticancer therapeutics and three thyroid cancer cell lines demonstrate the pro-survival effect of autophagy in thyroid cancer treatment. Although the present study only involved cell lines, it provides evidence for the beneficial combination of the anticancer therapeutic modalities with autophagy inhibitors, and proposes that autophagy inhibitors may serve as a possible adjunctive therapy for thyroid cancer.

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“…Zhang et al ( 96 ) found that pediatric AML bone marrow and cell lines exhibited a high expression of HMGB1, and miR-451 exerted tumor suppressive effects by targeting and modulating HMGB1 to enhance cell death and reduce autophagy in AML cells. In a study on thyroid cancer, the higher expression of HMGB1 was observed in vemurafenib-resistant thyroid cancer BCPAP-R cells ( 97 ). The overexpression of HMGB1 attenuated the sensitivity of BCPAP cells to vemurafenib by increasing cell viability and decreasing apoptosis and caspase-3 activity.…”

Section: Mechanisms Of Hmgb1 In Tumor Mdr Signalingmentioning

confidence: 99%

“…HMGB1 targeting inhibited vemurafenib-induced autophagy. Blocking the autophagy pathway with the autophagy inhibitor, 3-methyladenine, or knocking out HMGB1, sensitized BCPAP-R cells to vemurafenib ( 97 ). In a study on skin cancer, autocrine HMGB1 was found to regulate autophagy via a RAGE/HMGB1/ERK1/2-dependent pathway, thereby protecting keratinocytes from apoptosis upon UV irradiation ( 98 ).…”

Section: Mechanisms Of Hmgb1 In Tumor Mdr Signalingmentioning

confidence: 99%

Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review)

Shao

Zhu

et al. 2023

Int J Mol Med

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Tumor multidrug resistance (MDR) remains one of the most challenging barriers to successful cancer treatment. Several previous studies have suggested that high mobility group box 1 (HMGB1) may be a promising therapeutic target for overcoming cancer drug resistance. Emerging evidence has indicated that HMGB1 functions as a 'double-edged sword' that plays both pro- and anti-tumor roles in the development and progression of multiple types of cancer. HMGB1 has also been found to be a key regulator of several cell death and signaling pathways, and is involved in MDR by mediating cell autophagy and apoptosis, ferroptosis, pyroptosis and multiple signaling pathways. Additionally, HMGB1 is regulated by a variety of non-coding RNAs (ncRNAs), such as microRNAs, long ncRNAs and circular RNAs that are involved in MDR. Thus far, studies have been conducted to identify strategies with which to overcome HMGB1-mediated MDR by the targeted silencing of HMGB1 and the targeted interference of HMGB1 expression using drugs and ncRNAs. Therefore, HMGB1 is closely associated with tumor MDR and is a promising therapeutic target.

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Involvement of HMGB1 in vemurafenib resistance in thyroid cancer cells harboring BRAF (V600E) mutation by regulating excessive autophagy

Cited by 11 publications

References 29 publications

BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma

BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma

Re-evaluation of the role of autophagy in thyroid cancer treatment

Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review)

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