Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling

Wang, Lu; Du, Liqun; Xiong, Xi; Lin, Yusheng; Zhu, Jianlin; Yao, Ziting; Wang, Shuhong; Guo, Yi; Chen, Yuping; Geary, Kyla; Pan, Yunlong; Zhou, Fuyou; Gao, Shegan; Zhang, Dianzheng; Yeung, Sai‐Ching Jim; Zhang, Hao

doi:10.1038/s41388-021-01682-z

Cited by 21 publications

(23 citation statements)

References 38 publications

(16 reference statements)

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“…Six-week-old WT and A-P as chiRNA KI mice treated with tamoxifen were given 100 μg/mL carcinogen 4NQO (Cat. N8141, Sigma, St. Louis, MO, USA) in drinking water for 16 weeks [ 19 ]. Whole esophagi were longitudinally dissected and pictured.…”

Section: Methodsmentioning

confidence: 99%

Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model

Luo

Yao

et al. 2022

Cells

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Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of A-PaschiRNA in chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis of esophageal squamous cell carcinoma (ESCC). To our knowledge, we are the first to generate a chiRNA knockin mouse model using the Cre-loxP system. The model could be used to explore the roles of chiRNA in pathogenesis and potential targeted therapies.

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Section: Methodsmentioning

confidence: 99%

Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model

Luo

Yao

et al. 2022

Cells

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“…Real-Time PCR was performed as described previously ( Zhang et al, 2013 ; Wang et al, 2021a ). RNA was retro-transcribed using the FastQuant RT Kit (Tiangen, Beijing, China) following total RNA purification with TRIzol (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration

Dong

Xie

Jiang

et al. 2021

Front. Cell Dev. Biol.

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Tumor-derived exosomes, containing multiple nucleic acids and proteins, have been implicated to participate in the interaction between tumor cells and microenvironment. However, the functional involvement of phosphatases in tumor-derived exosomes is not fully understood. We and others previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) acts as a tumor suppressor in multiple cancer types. In addition, its role in tumor immune microenvironment remains elusive. Bioinformatical analyses revealed that PTPRO was closely associated with immune infiltration, and positively correlated to M1-like macrophages, but negatively correlated to M2-like macrophages in breast cancer tissues. Co-cultured with PTPRO-overexpressing breast cancer cells increased the proportion of M1-like tumor-associated macrophages (TAMs) while decreased that of M2-like TAMs. Further, we observed that tumor-derived exosomal PTPRO induced M1-like macrophage polarization, and regulated the corresponding functional phenotypes. Moreover, tumor cell-derived exosomal PTPRO inhibited breast cancer cell invasion and migration, and inactivated STAT signaling in macrophages. Our data suggested that exosomal PTPRO inhibited breast cancer invasion and migration by modulating macrophage polarization. Anti-tumoral effect of exosomal PTPRO was mediated by inactivating STAT family in macrophages. These findings highlight a novel mechanism of tumor invasion regulated by tumor-derived exosomal tyrosine phosphatase, which is of translational potential for the therapeutic strategy against breast cancer.

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“…The cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) is activated by nicotine and is a progression prognostic factor for ESCC. Metformin downregulated CHRNA7 and may be an option for treatment of nicotine-driven tumors [122].…”

Section: Head and Neck Cancermentioning

confidence: 99%

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

2022

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Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na+/I− symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.

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Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling

Cited by 21 publications

References 38 publications

Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model

Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model

Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

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