CYP3A5 suppresses metastasis of lung adenocarcinoma through ATOH8/Smad1 axis
Qixing Mao1,2, Lin Wang2,3, Yingkuan Liang1,2
1Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital Nanjing 210009, P. R. China.
Abstract:
Cytochrome P450 3A5 (CYP3A5) maintains primary roles in toxic metabolism, catalyzes redox reaction, and contributes to chemotherapeutic resistance. However, the mechanism of CYP3A5 in carcinogenesis remains largely undefined. Here, we investigated a novel role of CYP3A5 inhibiting the metastasis in lung adenocarcinoma (LUAD) via ATOH8/Smad1 axis. We found that CYP3A5 was generally down-regulated in LUAD by RT-PCR, western blot and immunohistochmeistry (IHC) in tissues and cell lines. Low expression of CYP3A5 was significantly associated with poor prognosis of LUAD patients. Functionally, ectopic expression of CYP3A5 could substantially inhibit the migration and invasion in vitro. Consistently, up-regulation of CYP3A5 dramatically suppressed metastatic ability in vivo. Mechanistically, high-throughput phosphorylation chip indicated that CYP3A5 significantly decreased the phosphorylation of Smad1, resulting in suppression of metastasis. Furthermore, bioinformatics analysis and co-immunoprecipitation (Co-IP) experiments uncovered that CYP3A5 interacted with ATOH8, and the interaction, in turn, mediated in-activation in the Smad1 pathway. The combined IHC panel, including CYP3A5 and phosphorylation of Smad1, exhibited a better prognostic value for LUAD patients than any of these components individually. Taken together, CYP3A5 repressed activation of Smad1 to inhibit LUAD metastasis via interacting with ATOH8, indicating a novel potential mechanism of CYP3A5 in LUAD progression.
Insights
Cytochrome P450 3A5 (CYP3A5) inhibits lung adenocarcinoma metastasis by down-regulating the Smad1 pathway through interaction with ATOH8. Low CYP3A5 expression predicts poor patient prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cytochrome P450 3A5 (CYP3A5) is involved in toxic metabolism and drug resistance.
- Its role in cancer development, particularly lung adenocarcinoma (LUAD) metastasis, is not well understood.
Purpose of the Study:
- To investigate the novel mechanism of CYP3A5 in inhibiting lung adenocarcinoma (LUAD) metastasis.
- To explore the involvement of the ATOH8/Smad1 signaling pathway.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry (IHC) were used to assess CYP3A5 expression in LUAD tissues and cell lines.
- In vitro and in vivo experiments evaluated the functional role of CYP3A5 in metastasis.
- High-throughput phosphorylation chip, bioinformatics analysis, and co-immunoprecipitation (Co-IP) were employed to elucidate the molecular mechanism.
Main Results:
- CYP3A5 expression was significantly down-regulated in LUAD tissues and associated with poor patient prognosis.
- Overexpression of CYP3A5 suppressed LUAD cell migration, invasion, and metastasis both in vitro and in vivo.
- CYP3A5 was found to interact with ATOH8, leading to decreased Smad1 phosphorylation and inactivation of the Smad1 pathway, thereby inhibiting metastasis.
- Combined analysis of CYP3A5 and phosphorylated Smad1 expression provided enhanced prognostic value for LUAD patients.
Conclusions:
- CYP3A5 plays a crucial role in suppressing LUAD metastasis by inhibiting the Smad1 pathway via interaction with ATOH8.
- CYP3A5 represents a potential therapeutic target for mitigating LUAD progression and metastasis.
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