Gastrodin overcomes chemoresistance via inhibiting Skp2-mediated glycolysis

by Selleckchem | Jan 18 2024

Aerobic glycolysis, a typical phenotype in human tumors, is associated with tumor progression and chemotherapy resistance. The present study demonstrated that cisplatin-resistant oral squamous cell carcinoma (OSCC) cells exerted a stronger glycolysis ability, which was associated with hexokinase 2 (HK2) overexpression. Additionally, the tumor growth of OSCC cells was delayed in vivo and the glycolysis was notably decreased following HK2 knockdown. The natural compound screening revealed that gastrodin could be an effective candidate for OSCC therapy since it inhibited HK2-mediated glucose metabolism and promoted endogenous OSCC cell apoptosis. Furthermore, gastrodin could bind to protein kinase B (Akt) and suppress its activity, thus downregulating HK2 at the transcriptional level. Additionally, S-phase kinase-associated protein 2 (Skp2) was highly expressed in OSCC cells, while K63-linked ubiquitination of Akt was inhibited in Skp2-depleted cisplatin-resistant OSCC cells. Gastrodin could also inhibit the cisplatin resistance of OSCC cells in vivo, particularly when combined with the Skp2 inhibitor, SZL P1-41. Overall, the aforementioned finding suggested that targeting the Skp2-Akt axis could be a potential therapeutic strategy for treating OSCC and overcoming chemoresistance.

Comments:

This study presents fascinating insights into potential therapeutic strategies for oral squamous cell carcinoma (OSCC) and overcoming resistance to cisplatin, a common chemotherapy drug. The findings highlight several key points:

1. **Glycolysis and HK2 Overexpression:** The increased glycolysis ability observed in cisplatin-resistant OSCC cells, linked to overexpression of hexokinase 2 (HK2), suggests a metabolic shift associated with chemotherapy resistance and tumor progression.

2. **Effect of Gastrodin:** Gastrodin emerges as a promising candidate for OSCC therapy. It demonstrates inhibitory effects on HK2-mediated glucose metabolism, induces apoptosis in OSCC cells, and influences Akt activity, ultimately downregulating HK2 at the transcriptional level.

3. **Skp2 and Ubiquitination of Akt:** The study also emphasizes the role of S-phase kinase-associated protein 2 (Skp2) in OSCC cells. Its high expression and inhibition of K63-linked ubiquitination of Akt contribute to cisplatin resistance.

4. **Combination Therapy Potential:** Gastrodin, when used in combination with the Skp2 inhibitor SZL P1-41, shows promise in inhibiting cisplatin resistance in OSCC cells, suggesting a potential synergistic effect.

5. **Therapeutic Implications:** Targeting the Skp2-Akt axis emerges as a potential therapeutic strategy for OSCC treatment and overcoming chemoresistance. Modulating this pathway could be a viable approach to enhance the efficacy of chemotherapy.

This research offers a multifaceted approach to tackling OSCC, addressing both metabolic shifts and specific molecular pathways involved in chemotherapy resistance. The identification of gastrodin as a potential therapeutic agent, particularly in combination with Skp2 inhibition, presents a novel direction for future therapeutic interventions in OSCC.