Xisha Chen

Resistance to paclitaxel-based chemotherapy represents a major clinic challenge in triple-negative breast cancer (TNBC). Insights on the regulation genes of chemoresistance and underlying mechanisms in TNBC are waiting for in-depth investigation to address the current treatment bottlenecks. In this study, we identified that ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) was preferentially overexpressed in TNBC and correlated with worse prognosis as well as poor response to chemotherapy. Upregulation of UCH-L1 attenuated the inhibitory effect of paclitaxel on tumor cells through modulating the aerobic glycolysis, while knockdown of UCH-L1 increased the responsiveness of TNBC cells to the drug both in vitro and in vivo. Coimmunoprecipitation results revealed that the N terminal of UCH-L1 interacts with the C-terminal domain of pyruvate kinase M2 (PKM2). UCH-L1 stabilized PKM2 via removing K48-linked polyubiquitination of PKM2 protein at K498, and thereby promoting glycolysis. Moreover, the expression levels of UCH-L1 and PKM2 were elevated in paclitaxel-resistant TNBC cells, and inhibition of UCH-L1/PKM2 axis-mediated glycolysis markedly sensitized the cells to paclitaxel treatment. Meanwhile, high expression of PKM2 was associated with shorter overall survival in TNBC patients who received chemotherapy. Clinically, PKM2 expression is positively correlated with the expression of UCH-L1 in TNBC tissues. In conclusion, our study reveals that high-expressed UCH-L1 was one of the biomarkers predicting and determining chemosensitivities of TNBC by advancing the cleavage of K48-linked polyubiquitin chains from PKM2 and enhancing glycolysis, and suggests that targeting UCH-L1/PKM2 axis holds great promise for reversing chemoresistance.

Tripterygium wilfordii Hook F (TWHF) is a traditional Chinese medicine with multifaceted pharmacological properties, has faced clinical application challenges due to its dose-limiting organ toxicity. Through a systematic analysis of current literature, this review deciphers the dual regulatory role of mitochondrial function in mediating both therapeutic efficacy and adverse effects of TWHF-derived active compounds. We elucidate that processes such as mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy and mitochondrial apoptosis pathways influence the therapeutic efficacy and adverse effects of TWHF active ingredients. In addition, we review innovative dosage forms and derivatives of TWHF that exploit mitochondrial targeting to enhance their pharmacological efficacy. This article offers a concise overview pharmacological and toxicological effects of the principal active components of TWHF, in particular triptolide and celastrol, with a particular emphasis on elucidating the critical role of mitochondria in these processes. Further high-quality basic studies are essential to strengthen the link between mitochondrial function and the active compounds of TWHF, offering more diverse options for their clinical development. Graphical Abstract

In the clinical management of cancers, the emergence of chemoresistance represents a profound and imperative “pain point” that requires immediate attention. Understanding the mechanisms of chemoresistance is essential for developing effective therapeutic strategies. Importantly, existing studies have demonstrated that glucose metabolic reprogramming, commonly referred to as the Warburg effect or aerobic glycolysis, is a major contributor to chemoresistance. Additionally, lactate, a byproduct of aerobic glycolysis, functions as a signaling molecule that supports lysine lactylation modification of proteins, which also plays a critical role in chemoresistance. However, it is insufficient to discuss the role of glycolysis or lactylation in chemoresistance from a single perspective. The intricate relationship between aerobic glycolysis and lactylation plays a crucial role in promoting chemoresistance. Thus, a thorough elucidation of the mechanisms underlying chemoresistance mediated by aerobic glycolysis and lactylation is essential. This review provides a comprehensive overview of these mechanisms and further outlines that glycolysis and lactylation exert synergistic effects, promoting the development of chemoresistance and creating a positive feedback loop that continues to mediate this resistance. The close link between aerobic glycolysis and lactylation suggests that the application of glycolysis-related drugs or inhibitors in cancer therapy may represent a promising anticancer strategy. Furthermore, the targeted application of lactylation, either alone or in combination with other treatments, may offer new therapeutic avenues for overcoming chemoresistance.

Breast cancer is the most commonly diagnosed malignancy and benefits from endocrine agents such as tamoxifen. However, the development of drug resistance in cancerous cells often leads to recurrence, thus limiting the therapeutic benefit. Identification of potential biomarkers that can predict response to tamoxifen and recognize patients who will clinically benefit from this therapy is urgently needed. In this study, we report that high collagen type XI alpha 1 (COL11A1) expression was associated with poor therapeutic response and prognosis in breast cancer patients treated with tamoxifen. To confirm the role of COL11A1 in the development of tamoxifen resistance, we established MCF-7/COL11A1 and T47D/COL11A1 cell lines, which stably expressed COL11A1. Compared with parental MCF-7 and T47D, MCF-7/COL11A1 and T47D/COL11A1 cells were more resistant to 4-OHT-induced growth inhibition. Moreover, the level of COL11A1 expression was upregulated in tamoxifen-resistant MCF-7/TamR and T47D/TamR cell lines, and depletion of COL11A1 markedly sensitized the cells to 4-OHT in vitro and in vivo. Interestingly, the level of estrogen receptor α (ERα) expression was elevated, probably due to the increased COL11A1 in TamR cells. In addition, knockdown of COL11A1 decreased the expression of ERα and its downstream target genes. Overall, our findings suggest that overexpressed COL11A1 contributes to tamoxifen resistance, and targeting COL11A1 holds great promise for reversing endocrine resistance.

With the continuous cognition of the relationship between tumor cells and tumor immune microenvironment, immunotherapy based on the immune checkpoint blockade has achieved great breakthroughs, led to improved clinical outcomes, and prolonged survival for cancer patients in recent years. Nevertheless, the de novo or acquired resistance to immunotherapy has greatly counteracted the efficacy, leading to a 20%–40% overall response rate. Thus, further in‐depth understanding of the regulation of the tumor microenvironment and antitumor immunity is urgently warranted. Ubiquitination‐mediated protein degradation plays vital roles in protein stabilization, activation, and dynamics as well as in cellular homeostasis modulation. The dysregulated ubiquitination and deubiquitination are closely related to the changes in physiological and pathological processes, which subsequently result in a variety of diseases including cancer. In this review, the authors first summarize the current knowledge about the involvement of the ubiquitin‐proteasome system in tumor development with the ubiquitin conjugation‐regulated stability of p53, phosphatase and tensin homolog, and Myc protein as examples, then dissect the potential implications of ubiquitination‐mediated immune checkpoints degradation in tumor microenvironment and immune responses, and finally discuss the effects of therapeutically targeting the ubiquitin‐proteasome pathway on immunotherapy, with the goal of providing deep insights into the exploitation of more precise and effective combinational therapy against cancer.