<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

Abstract

These authors contributed equally to this workBackground: Addiction to aerobic glycolysis is a common metabolic phenotype in human non-small cell lung cancer (NSCLC). The natural product Sinomenine (Sin) exhibits significant anti-tumor effects in various human cancers. However, the underlying mechanism remains elusive. Methods: The inhibitory effect of Sin on NSCLC cells was determined by MTS and soft agar assays. The glycolysis efficacy of NSCLC cells was examined by glucose uptake and lactate production. The activation of Akt signaling and the protein level of hexokinases II (HK2) were examined by immunoblot (IB), qRT-PCR, and immunohistochemical staining (IHC). The in vivo anti-tumor effect of Sin was validated by the xenograft mouse model. Results: We showed that HK2 is highly expressed in NSCLC tissues and cell lines. Depletion of HK2 suppressed cell viability, anchorage-independent colony formation, and xenograft tumor growth. Sinomenine exhibited a profound inhibitory effect on NSCLC cells by reducing HK2-mediated glycolysis both in vitro and in vivo. Ectopic overexpression of HK2 compromised these anti-tumor efficacies in sinomenine-treated NSCLC cells. Moreover, we revealed that sinomenine decreased Akt activity, which caused the downregulation of HK2-mediated glycolysis. Knockdown of Akt reduced HK2 protein level and impaired glycolysis. In contrast, overexpression of constitutively activated Akt1 reversed this phenotype. Conclusion: This study suggests that targeting HK2-mediated aerobic glycolysis is required for sinomenine-mediated anti-tumor activity.

Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells

“…Accumulating evidence has demonstrated that aerobic glycolysis is a key hallmark of cancer cells (9,10); molecules involved in the aerobic glycolysis pathway may be potential targets in cancer therapy, including cervical cancer (7,11). Therefore, certain metabolic enzymes such as Hexokinase 2, Phosphoinositide-Dependent Kinase 1 and Lactate dehydrogenase A chain (LDHA) involved in aerobic glycolysis have been identified as potential therapeutic targets (12)(13)(14)(15).…”

Advances in metformin‑based metabolic therapy for non‑small cell lung cancer (Review)

“…1 ): Glycolysis, which takes place under anaerobic conditions, and complete oxidation, which occurs under aerobic conditions ( 10 ). In the 1920s, Otto Heinrich Warburg discovered that cancer cells, unlike normal cells, use the glycolytic pathway to obtain energy for growth even in the presence of oxygen, which is a phenomenon known as ‘aerobic glycolysis’ or the Warburg effect ( 9 ), and aerobic glycolysis is a common metabolic phenotype in NSCLC ( 11 ). In positron emission tomography (PET)/CT, the high rate of glycolysis in NSCLC is reflected by the high uptake of 18F-fluorodeoxyglucose at the corresponding tumor sites ( 12 ).…”

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

“…The unfavorable prognosis (lower OS and DFS) was correlated with higher PKM2 expression, e.g., in breast, hepatocellular cancer, as well as in tongue and esophagus squamous cell carcinoma [ 189 – 192 ]. In correlation with glucose utilization, elevated HK2 was recently described in patients’ biopsies of esophageal, renal, lung, cervical, colon, and breast cancers [ 193 – 195 ]. The analyses of LDHA and PDK1 in situ protein expression also showed association with poor survival and therapy resistance in many malignancies (colon, breast, uterine, pancreas, lung, renal, gastric cancers, CNS malignancies, etc.).…”