Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

Hu, Ming; Huang, Tzu Ting; Chao, Tzu I.; Chen, Li Ju; Chen, Yen‐Lin; Tsai, M. H.; Liu, Chun Yu; Kao, Jia‐Horng; Chen, Kuen Feng

doi:10.1111/liv.13887

Cited by 8 publications

(3 citation statements)

References 39 publications

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“…PPP5C plays a crucial regulatory role in multiple signaling pathways through its interactions with various transcription factors and proteins. Dysregulation or abnormal activity of PPP5C is implicated in various diseases, including several cancers, obesity, and Alzheimer's disease [48][49][50][51][52]. Arylalkylamine N-acetyltransferase (AANAT) is a pivotal enzyme in the biosynthesis of melatonin, a crucial regulator of the circadian rhythm, playing a significant role in regulating the circadian clock and influencing various physiological processes, including sleep-wake cycles and seasonal behaviors [53].…”

Section: Discussionmentioning

confidence: 99%

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

Huang,

Wu,

et al. 2024

BMC Genomics

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Background Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. Methods Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). Results Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. Conclusions This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

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Section: Discussionmentioning

confidence: 99%

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

Huang,

Wu,

et al. 2024

BMC Genomics

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“…Research over the last two decades showed that cantharidin and its derivatives can promote tumor regression in multiple cancers via different mechanisms, and numerous analogues were designed to improve efficacy and safety in anti-cancer regimens [12,40]. Targets of cantharidin include protein phosphatases [41][42][43], glutathione S-transferases [44], STAT3 [16,45], Akt [46], and cell division control protein 1 (CDC1) [47]. With focus on the concomitant activation of EGFR and STAT3 as determinants of osteosarcoma progression, we investigated the mechanisms underlying the anticancer effects of SC, a cantharidin analogue, alone and in combination with the EGFR inhibitor erlotinib.…”

Section: Discussionmentioning

confidence: 99%

Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

2019

Aging

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Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Overactive EGFR signaling is frequently seen in osteosarcoma cells, and represents a potential therapeutic target. However, feedback activation of STAT3 after EGFR inhibition is linked to treatment resistance, suggesting that combined EGFR/STAT3 inhibition may be needed to overcome this effect. Cantharidin and its analogues have shown strong anticancer effects, including STAT3 inhibition, in several tumor cells. Therefore, we investigated the effects of sodium cantharidate (SC), either as monotherapy and in combination with the EGFR inhibitor erlotinib, on STAT3 activation and osteosarcoma cell growth. Cell viability, migration, and apoptosis assays were performed in human MG63 and U2OS cells, and MG63 xenografts were generated in nude mice to verify the suppression of tumor growth in vivo. Additionally, western blotting and immunohistochemistry were used to verify the STAT3 and EGFR phosphorylation statuses in xenografts. We found that SC repressed cell viability and migration and induced apoptosis in vitro, while combined SC and erlotinib treatment enhanced osteosarcoma growth suppression by preventing feedback activation of STAT3. These data support further development of cantharidin-based combination therapies for metastatic and recurrent/refractory osteosarcoma.

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“…However, its effects on PP1 at the micromolar level (similar to PP2A) and, more importantly, its inhibitory effects on PP5 at the nanomolar level could modulate these reported effects, and their contribution should be clarified [ 20 ]. In fact, PP5 has been demonstrated to play oncogenic functions in cholangiocarcinoma cell lines in vitro and in a xenograft model derived from the human liver bile duct carcinoma cell line HuCCT1 in vivo, at least in part directly binding and regulating AMPK activation [ 21 ]. These considerations are further supported by recent data in the literature demonstrating the opposite functions of PP2A and PP5 in human cancer in the regulation of key pathways such as MAPK signaling [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Role of the PP2A Pathway in Cholangiocarcinoma: State of the Art and Future Perspectives

Cristóbal

Lamarca

2022

Cancers

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Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

Abstract: Protein phosphatase 5 negatively regulates AMPK phosphorylation and contributes to CCA aggressiveness; thus, PP5 may be a potential therapeutic target in CCA.

Cited by 8 publications

References 39 publications

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

Sodium cantharidate targets STAT3 and abrogates EGFR inhibitor resistance in osteosarcoma

Role of the PP2A Pathway in Cholangiocarcinoma: State of the Art and Future Perspectives

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