Jalal Sajid, Zhang Ting, Deng Jia, Wang Jie, Xu Ting, Zhang Tianhua, Zhai Chuanxin, Yuan Ruqiang, Teng Hongming, Huang Lin
Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
Liaoning Provincial Key Laboratory of Medical Molecular Biology, Dalian, China.
Front Pharmacol. 2022 Aug 10;13:900973. doi: 10.3389/fphar.2022.900973. eCollection 2022.
Melanoma is a highly aggressive skin cancer and accounts for most of the skin cancer-related deaths. The efficacy of current therapies for melanoma remains to be improved. The isopropanolamine derivative of β-elemene LXX-8250 was reported to present better water solubility and stronger toxicity to tumor cells than β-elemene. Herein, LXX-8250 treatment showed 4-5-fold more toxicity to melanoma cells than the well-known anti-melanoma drug, Dacarbazine. LXX-8250 treatment induced apoptosis remarkably, which was caused by the impairment of autophagic flux. To clarify the molecular mechanism, microarray analyses were conducted, and PFKFB4 expression was found to be suppressed by LXX-8250 treatment. The cells overexpressed with PFKFB4 exhibited resistance to apoptosis induction and autophagic flux inhibition by LXX-8250 treatment. Moreover, LXX-8250 treatment suppressed glycolysis, to which the cells overexpressed with PFKFB4 were tolerant. LXX-8250 treatment inhibited the growth of melanoma xenografts and suppressed PFKFB4 expression and glycolysis . Taken together, LXX-8250 treatment induced apoptosis through inhibiting autophagic flux and glycolysis in melanoma cells, which was mediated by suppression of PFKFB4 expression. The study provides a novel strategy to melanoma treatment.
黑色素瘤是一种侵袭性很强的皮肤癌，占皮肤癌相关死亡的大多数。目前用于治疗黑色素瘤的疗法的疗效仍有待提高。据报道，β-榄香烯的异丙醇胺衍生物LXX-8250比β-榄香烯具有更好的水溶性和更强的肿瘤细胞毒性。在此，LXX-8250处理对黑色素瘤细胞的毒性比著名的抗黑色素瘤药物达卡巴嗪高4至5倍。LXX-8250处理显著诱导细胞凋亡，这是由自噬通量受损引起的。为了阐明分子机制，进行了微阵列分析，发现LXX-8250处理可抑制PFKFB4的表达。过表达PFKFB4的细胞对LXX-8250处理诱导的细胞凋亡和自噬通量抑制具有抗性。此外，LXX-8250处理抑制糖酵解，而过表达PFKFB4的细胞对糖酵解具有耐受性。LXX-8250处理抑制黑色素瘤异种移植瘤的生长，并抑制PFKFB4的表达和糖酵解。综上所述，LXX-8250处理通过抑制黑色素瘤细胞中的自噬通量和糖酵解诱导细胞凋亡，这是由PFKFB4表达的抑制介导的。该研究为黑色素瘤治疗提供了一种新策略。
