Xi Cheng

Whether under anaerobic or aerobic conditions, glycolysis results in production of lactate. Increasing evidence suggests that lactate serves as a multifunctional signaling molecule that develops non-metabolic activities in addition to serving as a key metabolite to link glycolysis and oxidative phosphorylation. Histone posttranslational modification patterns (HPTMs) are essential epigenetic processes controlling a variety of biological activities. Proteomics based on mass spectrometry (MS) has been used to progressively reveal new HPTMs. Recent discoveries of histone lactylation modification mediated by lactate and subsequent research demonstrating its involvement in cancer, inflammation, lung fibrosis, and other conditions suggest that it plays a significant role in immune regulation and homeostasis maintenance. This review provides a brief overview of the complicated control of histone lactylation modification in both pathological and physiological conditions.

Significance Immune checkpoint blockade (ICB) to reinvigorate cytotoxic T lymphocytes using antibodies against CTLA4 or PD1 generates durable therapeutic responses in patients across a variety of cancer types. However, some cancers such as castration-resistant prostate cancer (CRPC) show overwhelming resistance to ICB. Here, we develop a nitroproteomic approach and uncover a potential mechanism for the immunotherapy resistance where a key protein for T cell activation, lymphocyte-specific protein tyrosine kinase (LCK), is nitrated and inactivated by myeloid-derived suppressor cell–generated reactive nitrogen species (RNS) in the resistant tumor. An agent that neutralizes RNS significantly sensitizes CRPC to ICB therapy in a mouse model. Therefore, our studies illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of ICB-resistant cancers.

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, has been shown to promote anti-cancer action across a wide range of malignancies, including gastric, lung, and breast cancers. Our previous study showed that apatinib increases apoptosis in anaplastic thyroid carcinoma (ATC), but the direct functional mechanism of tumor lethality mediated by apatinib is still unknown. In this study, we demonstrated that apatinib induced both autophagy and apoptosis in human ATC cells through downregulation of p-AKT and p-mTOR signals via the AKT/mTOR pathway. Moreover, inhibition of apatinib-induced autophagy increased apatinib-induced apoptosis in ATC cells, and additional tumor suppression was critically produced by the combination of apatinib and the autophagy inhibitor chloroquine in vivo and in vitro. These findings showed that both autophagy and AKT/mTOR signals were engaged in ATC cell death evoked by apatinib. ATC patients might benefit from the new anti-cancer drug, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.

Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo. Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC.

Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.