Tryptophan metabolism induced by TDO2 promotes prostatic cancer chemotherapy resistance in a AhR/c-Myc dependent manner

by Selleckchem | Oct 25 2023

Background: Tumor cells exhibit enhanced metabolism of nutrients to satisfy the demand of sustained proliferation in vivo. Seminal reports have presented evidence that tryptophan (Trp) metabolic reprogramming induced by aberrant indoleamine 2,3-dioxygenases could promote tumor development in several cancer types. However, the underlying mechanism of Trp metabolism associated tumor progression is not fully understood.

Materials and methods: Prostatic cell lines LNCaP and VCaP were purchased from the Cell Bank of the Chinese Academy of Sciences (China). Human prostatic tumor tissue samples were obtained from the Tongji Hospital. Female NOD-SCID mice (6 ~ 8 weeks) were purchased from Huafukang Co. (China) and raised in SPF room. Commercial kits and instruments were used for cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis and other experiments.

Result: Comparing the tumor tissues from prostatic cancer patients, we found elevated expression of tryptophan 2, 3-dioxygenase 2 (TDO2), and elevated Trp metabolism in chemo-resistant tumor tissues. In vitro, overexpression of TDO2 significantly promoted the Trp metabolism in prostatic cancer cell lines LNCaP and VCap, resulting in the multidrug resistance development. Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment.

Conclusion: Our study demonstrates that elevated TOD2 expression promoted Trp metabolism and metabolite Kyn production, thus resulting in the activation of AhR/c-Myc/ABC-SLC transporters signaling pathway. Interrupt of Trp metabolism/c-Myc loop efficiently suppressed the drugs resistance induced by TDO2, which represented potential target to improve the outcome in drug-resistant prostatic cancer treatment.

Comments:

Background: Tumor cells have a heightened metabolic demand to support their proliferation, and the reprogramming of tryptophan (Trp) metabolism through indoleamine 2,3-dioxygenase (IDO) enzymes has been implicated in promoting tumor development in various cancer types. However, the specific mechanism by which Trp metabolism contributes to tumor progression remains unclear.

Materials and methods: We utilized prostatic cell lines LNCaP and VCaP obtained from the Cell Bank of the Chinese Academy of Sciences, as well as human prostatic tumor tissue samples from Tongji Hospital. Female NOD-SCID mice were acquired from Huafukang Co. and maintained in a specific pathogen-free (SPF) environment. We employed commercial kits and instruments for various experimental analyses, including cell apoptosis analysis, real-time PCR, western blotting, ELISA analysis, and more.

Results: Through a comparison of tumor tissues from patients with prostatic cancer, we observed elevated expression of tryptophan 2,3-dioxygenase 2 (TDO2) and increased Trp metabolism in chemo-resistant tumor tissues. In vitro experiments involving overexpression of TDO2 in prostatic cancer cell lines LNCaP and VCaP showed significant promotion of Trp metabolism, leading to the development of multidrug resistance. Mechanistically, we demonstrated that the Trp metabolite kynurenine (Kyn) facilitated the upregulation and nuclear translocation of the transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-κB to activate the oncogenic protein c-Myc. In turn, c-Myc promoted the upregulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and increased Trp metabolism in prostatic cancer. Interrupting the Trp/TDO2/Kyn/AhR/c-Myc loop with the c-Myc inhibitor Mycro-3 efficiently suppressed chemoresistance and improved the outcomes of chemotherapy, representing a novel strategy in the clinical treatment of prostatic cancer.

Conclusion: Our study demonstrates that elevated TDO2 expression promotes Trp metabolism and the production of the metabolite Kyn, subsequently activating the AhR/c-Myc/ABC-SLC transporters signaling pathway. Disrupting the Trp metabolism/c-Myc loop effectively suppresses drug resistance induced by TDO2, thereby representing a potential target for improving outcomes in drug-resistant prostatic cancer treatment.