Dissecting the novel abilities of aripiprazole: The generation of anti-colorectal cancer effects by targeting Gαq via HTR2B

Liu, Haowei; Qiuming, Huang; Fan, Yingjun; Li, Bo; Liu, Xuemei; Hu, Changhua

doi:10.1016/j.apsb.2023.05.015

Cited by 4 publications

(2 citation statements)

References 42 publications

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“… 59 5‐HT stimulates the growth but inhibits apoptosis of CRC cells through a variety of 5‐HTRs. 60 , 61 , 62 , 63 , 64 HCC cells express different serotonin receptors, which were demonstrated to increase tumour cell proliferation and metastasis. 44 , 65 5‐HT also inhibited autophagy through HTR2B in HCC, leading to continuous phosphorylation of p70s6k and 4E‐BP1, two downstream targets of mammalian target of rapamycin (mTOR).…”

Section: Serotonin's Pro‐tumourigenic Roles In Cancer Cellsmentioning

confidence: 99%

Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities

Chen,

Huang,

et al. 2024

Clinical & Translational Med

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BackgroundSerotonin (5‐hydroxytryptamine) is a multifunctional bioamine serving as a neurotransmitter, peripheral hormone and mitogen in the vertebrate system. It has pleiotropic activities in central nervous system and gastrointestinal function via an orchestrated action of serotonergic elements, particularly serotonin receptor‐mediated signalling cascades. The mitogenic properties of serotonin have garnered recognition for years and have been exploited for repurposing serotonergic‐targeted drugs in cancer therapy. However, emerging conflicting findings necessitate a more comprehensive elucidation of serotonin's role in cancer pathogenesis.Main body and conclusionHere, we provide an overview of the biosynthesis, metabolism and action modes of serotonin. We summarise our current knowledge regarding the effects of the peripheral serotonergic system on tumourigenesis, with a specific emphasis on its immunomodulatory activities in human cancers. We also discuss the dual roles of serotonin in tumour pathogenesis and elucidate the potential of serotonergic drugs, some of which display favourable safety profiles and impressive efficacy in clinical trials, as a promising avenue in cancer treatment.Key points Primary synthesis and metabolic routes of peripheral 5‐hydroxytryptamine in the gastrointestinal tract. Advanced research has established a strong association between the serotonergic components and carcinogenic mechanisms. The interplay between serotonergic signalling and the immune system within the tumour microenvironment orchestrates antitumour immune responses. Serotonergic‐targeted drugs offer valuable clinical options for cancer therapy.

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Section: Serotonin's Pro‐tumourigenic Roles In Cancer Cellsmentioning

confidence: 99%

Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities

Chen,

Huang,

et al. 2024

Clinical & Translational Med

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“…Multiple carcinogenic events, including serrated adenomas, adenoma-carcinoma sequence, and inflammation, contribute to the development of CRC 4 , 5 . The initiation of sporadic CRC is largely attributed to acquired somatic genetic mutations or epigenetic alterations induced by modifiable risk factors 6 , 7 , 8 , 9 . It is necessary to identify novel genes involved in the pathogenesis of CRC in order to develop effective treatments.…”

Section: Introductionmentioning

confidence: 99%

Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

Xu,

Xi,

Kim

et al. 2024

Acta Pharmaceutica Sinica B

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The Antipsychotic Drug Aripiprazole Suppresses Colorectal Cancer by Targeting LAMP2a to Induce RNH1/miR‐99a/mTOR‐Mediated Autophagy and Apoptosis

Hu,

Fu,

Han

et al. 2024

Advanced Science

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The mammalian target of rapamycin (mTOR) is a critical signaling hub for sustaining cancer survival. Targeting mTOR and inducing autophagic cell death downstream of it represent promising therapeutic strategies for cancer prevention. A US Food and Drug Administration‐approved drug library containing 616 small molecules is used to screen anticancer drugs against colorectal cancer (CRC) cells that rely on mTOR. This led to the identification of an antipsychotic drug aripiprazole, which significantly induced mTOR inhibition and autophagic apoptosis in CRC, in vitro and in vivo. The use of drug affinity response target stability identified lysosome‐associated membrane protein 2A (LAMP2a) as a direct target of aripiprazole. LAMP2a‐deficient CRC cells are refractory to aripiprazole. High LAMP2a expression is associated with poor survival of patients with CRC and negatively correlated with expression of ribonuclease inhibitor 1 (RNH1), which is later confirmed as a novel substrate of LAMP2a. Mechanistically, aripiprazole bound to the Lys401–His404 of LAMP2a and repressed its activity, subsequently inactivating RNH1/miR‐99a/mTOR signaling and inducing autophagy‐mediated apoptosis, thereby suppressing tumorigenesis. Liposome‐mediated delivery of aripiprazole in combination with fluorouracil elicited superior therapeutic benefits in CRC, as compared to single treatments, thereby highlighting that aripiprazole may be repurposed as a novel therapeutic agent for CRC treatment.

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Dissecting the novel abilities of aripiprazole: The generation of anti-colorectal cancer effects by targeting Gαq via HTR2B

Cited by 4 publications

References 42 publications

Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities

Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities

Sulfation of chondroitin and bile acids converges to antagonize Wnt/β-catenin signaling and inhibit APC deficiency-induced gut tumorigenesis

The Antipsychotic Drug Aripiprazole Suppresses Colorectal Cancer by Targeting LAMP2a to Induce RNH1/miR‐99a/mTOR‐Mediated Autophagy and Apoptosis

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