Resistance to HER2-targeted therapy represents a significant challenge for the successful treatment of breast cancer patients with HER2-positive tumors. Through a global mass spectrometry-based proteomics approach, we discovered that the expression of the N6-methyladenosine (m6A) demethylase ALKBH5 was significantly upregulated in HER2-targeted therapy-resistant breast cancer cells. Elevated expression of ALKBH5 was sufficient to confer resistance to HER2-targeted therapy, and specific knockdown of ALKBH5 rescued the efficacy of trastuzumab and lapatinib in resistant breast cancer cells. Mechanistically, ALKBH5 promoted m6A demethylation of GLUT4 mRNA and increased GLUT4 mRNA stability in a YTHDF2-dependent manner, resulting in enhanced glycolysis in resistant breast cancer cells. In breast cancer tissues obtained from patients with poor response to HER2-targeted therapy, increased expression of ALKBH5 or GLUT4 was observed and was significantly associated with poor prognosis in the patients. Moreover, suppression of GLUT4 via genetic knockdown or pharmacological targeting with a specific inhibitor profoundly restored the response of resistant breast cancer cells to trastuzumab and lapatinib both in vitro and in vivo. In conclusion, ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes resistance to HER2-targeted therapy, and targeting the ALKBH5/GLUT4 axis has therapeutic potential for treating breast cancer patients refractory to HER2-targeted therapies.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo . Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL.

Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Background Mucosal-associated invariant T (MAIT) cells are innate-like T cells, some studies have reported that the number of circulating MAIT cells reduced in patients with acute graft-versus-host-disease (aGVHD) development. However, the role of donor MAIT cells on aGVHD development and subsequent functional change still remain unclear. Methods The study recruited 86 patients with hematological malignancies who underwent allogeneic hematopoietic cell transplantation (HCT) from May 1, 2018 to June 30, 2019. MAIT cells, their subset, and cytokine levels were measured by flow cytometry. Gray’s test was used to assess the impact of graft MAIT cell proportion and number on aGVHD incidence. The Cox proportional hazard model was used in the multivariate analysis. The comparison for continuous variables was assessed using Mann–Whitney analysis. RNA-sequencing was performed to investigate the possible molecular pathway changes. Results Our study showed that the proportion of MAIT cells in grafts was not different from normal controls, but the CD4/8 subsets were altered. Taking the median of the proportion and number of MAIT cells in the graft as the threshold, the results showed that the incidence of grade B-D aGVHD in patients with MAIT cell proportion ≥ 3.03% was significantly higher than that in patients with MAIT cell proportion < 3.03% (56.3%, 95% CI 37.1–71.2 versus 23.1%, 95% CI 13.8–46.2; P = 0.038).The number of MAIT cells in the graft was not associated with aGVHD development (P = 0.173), however, when the graft contained more CD4 positive, CD8 positive, and CD4/CD8 double-positive MAIT cells, the incidence of aGVHD was significantly increased (P = 0.019, P = 0.035 and P = 0.027, respectively). Besides, reduced frequencies and counts of circulating MAIT cells were observed in patients with aGVHD when compared to patients without aGVHD, accompanied by enhanced production of Tumor necrosis factor-α, Interferon-γ and upregulated programmed death-1, CXC Chemokine Receptor-6 (CXCR6) and CD38 expression. Gene set enrichment analysis of MAIT cell RNA-seq data showed interferon-α response pathway upregulated in aGVHD patients when compared with patients without aGVHD and healthy controls. Conclusions Our study shows that MAIT cells in grafts and peripheral blood are both closely related to the aGVHD development post allogeneic HCT. Interferon-α response pathway perhaps is a critical regulation mechanism for the MAIT cell involvement in aGVHD development.