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Targeting the IDO-BCL2A1-Cytochrome c Pathway Promotes Apoptosis in Oral Squamous Cell Carcinoma
Qiaoping Zheng1, Guifang Gan1, Xianfu Gao2
1Department of Clinical Immunology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China.
Purpose:
Indolamine 2,3-dioxygenase (IDO) is the rate limiting enzyme of tryptophan degradation and is a negative prognostic factor in oral squamous cell carcinoma (OSCC) patients, while the underlying molecular mechanism remains unclear. This research aimed to explore the IDO expression and its biological functions in OSCC.
Materials And Methods:
IDO expression was analyzed by qPCR, Western blots, and immunohistochemistry (IHC) in OSCC cell lines and tissue specimens. Tryptophan and kynurenine content were determined by UPLC-MS/MS in serum samples of OSCC patients and healthy controls. Oncomine databases and Kaplan-Meier survival analyses were used to identify the IDO expression and its correlation with OSCC prognosis. Cell counting, CCK8 assay, flow cytometry, cell cycle, and EdU incorporation assays were used to assess the effect of IDO inhibition on OSCC growth either by shRNA or the IDO-specific inhibitor (epacadostat) in vitro. An OSCC xenograft mouse model was established to verify the predicted function of IDO inhibition in vivo. Mechanistically, an 84-gene apoptosis PCR array and rescue experiment were used to characterize the underlying mechanism involved in IDO-regulated apoptosis in OSCC.
Results:
IDO expression was upregulated in OSCC cell lines and tissues and was negatively correlated with OSCC progression. Lentivirus-mediated IDO knockdown and epacadostat significantly reduced viability and promoted apoptosis of OSCC cells in vitro and in vivo. The apoptosis PCR array identified BCL2 related protein A1 (BCL2A1) as the most obviously changed gene at the transcriptional level. IDO inhibition downregulated BCL2A1 expression, increased the expression and translocation of cytochrome c, thus promoted apoptosis in OSCC. Overexpression of BCL2A1 reversed the pro-apoptotic effect of IDO inhibition.
Conclusion:
The present results revealed that IDO directly affect the growth of OSCC cells by regulating BCL2A1 expression. IDO and the IDO-BCL2A1-cytochrome c axis may be potential therapeutic targets for OSCC.
Insights
Indolamine 2,3-dioxygenase (IDO) is upregulated in oral squamous cell carcinoma (OSCC) and drives tumor growth. Inhibiting IDO, by targeting the IDO-BCL2A1-cytochrome c axis, shows promise for OSCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Indolamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in tryptophan degradation.
- IDO is a known negative prognostic factor in oral squamous cell carcinoma (OSCC).
- The precise molecular mechanisms underlying IDO's role in OSCC remain largely unknown.
Purpose of the Study:
- To investigate the expression patterns of IDO in OSCC.
- To elucidate the biological functions and molecular mechanisms of IDO in OSCC.
- To evaluate IDO as a potential therapeutic target for OSCC.
Main Methods:
- IDO expression was quantified using qPCR, Western blots, and immunohistochemistry in OSCC cell lines and tissues.
- Tryptophan and kynurenine levels were measured in patient serum via UPLC-MS/MS.
- In vitro and in vivo studies assessed the impact of IDO inhibition (shRNA, epacadostat) on OSCC cell viability, apoptosis, and tumor growth, including mechanistic studies using an apoptosis PCR array.
Main Results:
- IDO expression was significantly upregulated in OSCC tissues and cell lines, correlating negatively with tumor progression.
- IDO inhibition, via genetic knockdown or epacadostat, reduced OSCC cell viability and promoted apoptosis both in vitro and in vivo.
- IDO inhibition downregulated BCL2A1 expression, leading to increased cytochrome c release and subsequent apoptosis; BCL2A1 overexpression rescued this effect.
Conclusions:
- IDO directly influences OSCC cell growth by modulating BCL2A1 expression.
- The IDO-BCL2A1-cytochrome c pathway is a critical regulator of apoptosis in OSCC.
- Targeting IDO and the identified axis presents a promising therapeutic strategy for OSCC.
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