Lomerizine 2HCl inhibits cell proliferation and induces protective autophagy in colorectal cancer via the PI3K/Akt/mTOR signaling pathway

Tan, Xiangpeng; He, Yan; Huang, Yun-Na; Zheng, Can‐Can; Li, Junqi; Liu, Qinwen; He, Ming‐Liang; Li, Bin; Xu, Wenwen

doi:10.1002/mco2.83

Cited by 15 publications

(10 citation statements)

References 44 publications

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“…The Akt/mTOR signaling is the main negative regulator of autophagy, and participates in regulating tumor proliferation [16,45]. In the present study, OXI restrained the Akt/mTOR axis, as demonstrated by the decreased phosphorylation levels of Akt and mTOR.…”

Section: Discussionsupporting

confidence: 59%

Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest

Shi¹,

Zhou²,

Huang³

et al. 2022

Int. J. Biol. Sci.

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Colorectal cancer (CRC) is one of the most common malignancies worldwide, yet successful treatment still remains a challenge. In this study, we found that oxiconazole (OXI), a broad-spectrum antifungal agent, exhibits certain anti-tumor effect against CRC. Autophagy arrest and subsequent apoptosis are characterized as pivotal events involving OXI-induced growth suppression of CRC cells. Mechanistically, OXI downregulates the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme, for reactive oxygen species (ROS) detoxication, to initiate autophagy by inactivating the Akt/mTOR pathway and inhibiting RAB7A-mediated fusion of autophagosome and lysosome, which lead to extreme accumulation of autophagosomes and subsequent growth suppression of CRC cells. Consistently, interfering with autophagy or overexpressing PRDX2 significantly impedes OXI-induced growth suppression of CRC cells. Moreover, OXI plus oxaliplatin, a mainstay drug for CRC treatment, achieves an improved anti-tumor effect. Taken together, our findings bring novel mechanistic insights into OXI-induced autophagy arrest and the growth inhibitory effect on CRC cells, and suggest a promisingly therapeutic role of OXI for CRC treatment.

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Section: Discussionsupporting

confidence: 59%

Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest

Shi¹,

Zhou²,

Huang³

et al. 2022

Int. J. Biol. Sci.

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“…Gene profiles were analyzed by the DESeq R software package (1.10.1), and genes with a fold change >2 were deemed differentially expressed genes. [ 2 ]…”

Section: Methodsmentioning

confidence: 99%

“…[ 1 ] In addition to the high incidence, the limited choice of chemotherapeutic drugs also contributes to the high mortality rate of CRC patients. [ 2 ] There is an urgent need to develop effective and low‐toxicity drugs to combat CRC. More than 90% of CRC patients have constitutive activation of the Wnt/ β ‐catenin pathway due to adenomatous polyposis coli (APC) or β ‐catenin mutations, which disrupts the cytoplasmic β ‐catenin destruction complex and leads to the nuclear translocation of β ‐catenin.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Nuclear β‐Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal Tumorigenesis

et al. 2022

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Colorectal cancer (CRC) is one of the most common malignant tumors in the world, with high prevalence and low 5-year survival. Most of the CRC patients show excessive activation of the Wnt/𝜷-catenin pathway which is a vital target for CRC treatment. Based on multiple CRC cell lines with different nuclear expression of 𝜷-catenin, NU2058 is identified from a small molecule library consisting of 280 bioactive compounds and found to selectively inhibit the proliferation of CRC cells with nuclear 𝜷-catenin activation in vitro and in vivo. The translational significance of NU2058 alone or in combination with chemotherapeutic drugs oxaliplatin and irinotecan (SN38) in CRC is demonstrated in orthotopic tumor model and patient-derived xenograft models. By integrating limited proteolysis-small molecule mapping (LiP-SMap) and mass spectrometry (MS), Ran-binding protein 3 (RanBP3) is identified as the direct target of NU2058. The results show that RanBP3 is a tumor suppressor in CRC and is associated with patient survival. Mechanistically, NU2058 increases the interaction of RanBP3 and 𝜷-catenin to promote nuclear export of 𝜷-catenin, which further inhibits transcription of c-Myc and cyclin D1 to induce cell senescence. Collectively, NU2058 may serve as a promising therapeutic agent for CRC patients with selective disruption of pathologic Wnt/𝜷-catenin signaling.

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“… 197 Meanwhile, an inhibition of the PI3K–AKT signaling axis can sensitize cancer cells to induce ferroptosis. 198 This sensibility requires the help of mTOR that is also the important downstream molecule of AMPK signaling pathway. 110 In xenograft mouse models for PI3K‐mutated breast cancer and PTEN‐defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near‐complete tumor regression.…”

Section: Molecular Signaling Pathways On Vcmentioning

confidence: 99%

“…Recent study has proved that glucagon‐like peptide‐1 exerted multiple cardioprotective functions such as regulation of osteoblastic transformation and calcification of VSMCs through the activation of PI3K‐AKT signaling 197 . Meanwhile, an inhibition of the PI3K–AKT signaling axis can sensitize cancer cells to induce ferroptosis 198 . This sensibility requires the help of mTOR that is also the important downstream molecule of AMPK signaling pathway 110 .…”

Section: Molecular Signaling Pathways On Vcmentioning

confidence: 99%

Vascular calcification: Molecular mechanisms and therapeutic interventions

Pan

Jie

Huang

2023

MedComm

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Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life‐threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin–angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.

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Lomerizine 2HCl inhibits cell proliferation and induces protective autophagy in colorectal cancer via the PI3K/Akt/mTOR signaling pathway

Cited by 15 publications

References 44 publications

Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest

Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest

Blockade of Nuclear β‐Catenin Signaling via Direct Targeting of RanBP3 with NU2058 Induces Cell Senescence to Suppress Colorectal Tumorigenesis

Vascular calcification: Molecular mechanisms and therapeutic interventions

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