Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance.

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

https://www.mdpi.com/2076-3921/10/3/349/pdf

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Background Ferroptosis is essential to regulate tumor growth and serves as a promising therapeutic target to lung cancer. Ubiquitin-specific protease 35 (USP35) belongs to the deubiquitinases family that is associated with cell proliferation and mitosis. In this research, we aim to elucidate the potential role and molecular basis of USP35 in lung cancer. Methods Lung cancer cells were infected with lentiviral vectors to silence or overexpress USP35. Cell viability, colony formation, lipid reactive oxygen species production, intracellular iron metabolism, and other ferroptotic markers were detected. The role of USP35 on ferroptosis and tumor progression were also tested in mouse tumor xenograft models in vivo. Results USP35 was abundant in human lung cancer tissues and cell lines. USP35 knockdown promoted ferroptosis, and inhibited cell growth, colony formation, and tumor progression in lung cancer cells. USP35 overexpression did not affect tumorigenesis and ferroptosis under basal conditions, but reduced erastin/RSL3-triggered iron disturbance and ferroptosis, thereby facilitating lung cancer cell growth and tumor progression. Further studies determined that USP35 directly interacted with ferroportin (FPN) and functioned as a deubiquitinase to maintain its protein stability. More importantly, we observed that USP35 knockdown sensitized lung cancer cells to cisplatin and paclitaxel chemotherapy. Conclusion USP35 modulates ferroptosis in lung cancer via targeting FPN, and it is a promising therapeutic target to lung cancer.

Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin.

Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance.

Tumor microenvironment and metabolic remodeling in gemcitabine-based chemoresistance of pancreatic cancer.

Chronic inflammation is a key driver for colitis-associated colorectal cancer. 5-hydroxytryptamine (5-HT), a neurotransmitter, has been reported to promote inflammation in the gastrointestinal tract. However, the mechanism behind this remains unclear. In this study, we found that 5-HT levels, as well as the expression of tryptophan hydroxylase 1 (TPH1), the 5-HT biosynthesis rate-limiting enzyme, were significantly upregulated in colorectal tumor tissues from patients with colorectal cancer, colorectal cancer mouse models, and colorectal cancer cell lines when compared with normal colorectal tissues or epithelial cell lines. Colorectal cancer cell-originated 5-HT enhanced NLRP3 inflammasome activation in THP-1 cells and immortalized bone marrow-derived macrophages (iBMDM) via its ion channel receptor, HTR3A. Mechanistically, HTR3A activation led to Ca2+ influx, followed by CaMKIIα phosphorylation (Thr286) and activation, which then induced NLRP3 phosphorylation at Ser198 (mouse: Ser194) and inflammasome assembling. The NLRP3 inflammasome mediated IL1β maturation, and release upregulated 5-HT biosynthesis in colorectal cancer cells by inducing TPH1 transcription, revealing a positive feedback loop between 5-HT and NLRP3 signaling. Silencing TPH1 or HTR3A by short hairpin RNA slowed down tumor growth in an established CT26 and iBMDM coimplanted subcutaneous allograft colorectal cancer mouse model, whereas treatment with TPH1 inhibitor 4-chloro-DL-phenylalanine or HTR3A antagonist tropisetron alleviated tumor progression in an azoxymethane/dextran sodium sulfate-induced colorectal cancer mouse model. Addressing the positive feedback loop between 5-HT and NLRP3 signaling could provide potential therapeutic targets for colorectal cancer.

Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation

The human HEAT repeat-containing protein 1 (HEATR1), consisting of 2144 amino acids, is a member of the UTP10 family and contains one HEAT repeat at its C-terminal. HEATR1 has been reported to regulate cytotoxic T lymphocytes and rRNA synthesis, while its functions in tumors are poorly understood. Here, we found that HEATR1 competed with Keap1 for binding to p62/sequestosome 1 (SQSTM1), resulted in up-regulation of Keap1, which then inhibited Nrf2 signaling in pancreatic cancer cells. HEATR1 knockdown enhanced proliferation and gemcitabine resistance of pancreatic cancer cells. Moreover, HEATR1 deficiency significantly improved xenografts growth and led to gemcitabine resistance in pancreatic cancer cell-derived xenografts through up-regulating Nrf2 signaling. By analyzing tumor tissue samples from pancreatic cancer patients, we found that low expression of HEATR1 was closely correlated with poor prognosis and clinicopathological features. Collectively, we suggest that HEATR1 deficiency promotes proliferation and gemcitabine resistance of pancreatic cancer through up-regulating Nrf2 signaling, indicating that HEATR1 may be a promising therapeutic target for pancreatic cancer.

HEATR1 deficiency promotes pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling.

Flumethasone enhances the efficacy of chemotherapeutic drugs in lung cancer by inhibiting Nrf2 signaling pathway.

Supramolecular nanomedicines based on self-assembly of D-peptides have been of great interest as potential candidates for cancer therapy. Neuropilin-1 (NRP1) and mouse double minute 2 (MDM2) have been considered as the anticancer targets because of their overexpression in cancers. However, NRP1/MDM2-targeted D-peptide supramolecular nanomedicines remain unreported. Here, a potent anticancer D-peptide supramolecular nanomedicine targeting NRP1 and MDM2, termed as NMTP-5, is identified by using structure-based virtual screening techniques. NMTP-5 exhibits good biostability and strong cellular uptake performance. Moreover, NMTP-5 displays strong anticancer activity to SK-Hep-1 cells in vitro and in vivo, with no apparent host toxicity. This work demonstrates that NMTP-5 can be used as a potential chemotherapeutic agent for the treatment of liver cancer.

An NRP1/MDM2-Targeted D-Peptide Supramolecular Nanomedicine for High-Efficacy and Low-Toxic Liver Cancer Therapy.

Bendamustine (BEN) is a FDA-approved bifunctional DNA-alkylating chemotherapy drug, but it suffers from short half-life, instability, and poor biocompatibility in the clinical application. Due to unique biostability of d-amino acid-containing peptides (D-peptides), constructing D-peptide-small molecule drug conjugates is emerging as a promising strategy for cancer therapy. Here, a high-affinity MDM2-targeted D-peptide (peptide 5) is discovered by applying structure-based drug design (SBDD). Taking the advantages of d-amino acids, a novel self-assembling D-peptide-small molecule drug conjugate (BEN-FF-peptide 5) is developed by simultaneously conjugating small molecule drug BEN and peptide 5 to the self-assembling peptide. In vitro results demonstrate that BEN-FF-peptide 5 exhibits superior cellular uptake ability, good biostability in human serum and strong inhibitory effect on the growth of human breast cancer (MCF-7) cells. In vivo study reveals that BEN-FF-peptide 5 significantly inhibits the growth of MCF-7 cells-derived xenograft in nude mice with no obvious side effects. This work provides a useful strategy to construct D-peptide-small molecule drug conjugates for high-efficacy and low-toxicity cancer therapy.

Yaxin Chen

Papers

Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation

HEATR1 deficiency promotes pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling.

Flumethasone enhances the efficacy of chemotherapeutic drugs in lung cancer by inhibiting Nrf2 signaling pathway.

An NRP1/MDM2-Targeted D-Peptide Supramolecular Nanomedicine for High-Efficacy and Low-Toxic Liver Cancer Therapy.

A Supramolecular Nanomedicine Based on Bendamustine and MDM2-Targeted D-peptide Inhibitor for Breast Cancer Therapy.