Cholesterol depletion sensitizes gallbladder cancer to cisplatin by impairing DNA damage response

Zhang, Yonglong; Liu, Yanfeng; Duan, Jinlin; Wang, Hui; Zhang, Yuchen; Qiao, Kun; Wang, Jian

doi:10.1080/15384101.2019.1676581

Cited by 43 publications

(36 citation statements)

References 48 publications

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“…Preparation of hollow zeolite structures without using macrotemplate has been reported. 698,699 Han et al 698 synthesized hollow sodalite spheres and NaA crystals by introducing crosslinked polyacrylamide (C-PAM) hydrogels into zeolite synthesis gels. The three-dimensional C-PAM networks with adjustable pore sizes provide unique scaffolds for zeolite nucleation and growth, which produces hollow zeolite structures due to the operation of a surface-to-core zeolite crystallization process ( Fig.…”

Section: Hierarchically Micro-macroporous Structuresmentioning

confidence: 99%

Hierarchically porous materials: synthesis strategies and structure design

et al. 2017

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Section: Hierarchically Micro-macroporous Structuresmentioning

confidence: 99%

Hierarchically porous materials: synthesis strategies and structure design

et al. 2017

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“…Despite recent progress regarding the diagnosis and prognosis of gallbladder cancer (GBC), ( 24‐26 ) the lack of effective diagnostic biomarkers and intrinsic chemoresistance to first‐line drugs results in an extremely poor prognosis of GBC patients. ( 27‐31 ) Therefore, continued efforts are required for identification of reliable tumor markers that will facilitate the early detection of GBC, as well as effective cellular targets that might provide the basis for therapeutic approaches. However, the roles of ceramides and their clinical relevance in gallbladder tumorigenesis are still open for study.…”

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confidence: 99%

C24‐Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5‐Phosphate 4‐Kinase Type‐2 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation

et al. 2020

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Background and Aims The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated. Approach and Results In the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) of de novo ceramide biosynthesis and length‐specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24‐Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24‐Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C24‐Ceramide promoted GBC cell proliferation and migration in vitro and in vivo. Mechanistically, C24‐Ceramide directly bound to phosphatidylinositol 5‐phosphate 4‐kinase type‐2 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6‐Ceramide, an analogue of natural ceramide, competed with C24‐Ceramide for PIP4K2C binding, thereby abrogating C24‐Ceramide–mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6‐Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells in vitro and in vivo, which was dependent on PIP4K2C. Conclusions Our findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24‐Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6‐Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24‐Ceramide.

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“…Suppression of cholesterol biosynthesis by lovastatin could inhibit GBC cell proliferation, possibly through attenuating the DDR process. 266 Abdel-Wahab et al 267 have clustered 20 "direct" DDR genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that regulate DDR process (BAP1, CDK12, MLL3, TP53, BLM) in BTC (270 ICC, 60 ECC, and 92 GBC specimens) by hybrid capture-based NGS. BRCA-associated BTC is uncommon as BRCA1/2 mutations were detected in 4.0% of 353 GBC samples by Spizzo.…”

Section: Pd-1/pd-l1mentioning

confidence: 99%

“…Suppression of cholesterol biosynthesis by lovastatin could inhibit GBC cell proliferation, possibly through attenuating the DDR process. 266 …”

Section: Targeted Therapy Of Gbcmentioning

confidence: 99%

Overview of current targeted therapy in gallbladder cancer

Song

et al. 2020

Sig Transduct Target Ther

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Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.

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Cholesterol depletion sensitizes gallbladder cancer to cisplatin by impairing DNA damage response

Cited by 43 publications

References 48 publications

Hierarchically porous materials: synthesis strategies and structure design

Hierarchically porous materials: synthesis strategies and structure design

C24‐Ceramide Drives Gallbladder Cancer Progression Through Directly Targeting Phosphatidylinositol 5‐Phosphate 4‐Kinase Type‐2 Gamma to Facilitate Mammalian Target of Rapamycin Signaling Activation

Overview of current targeted therapy in gallbladder cancer

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