Tian Maojin, Yang Le, Zhao Ziqian, Li Jigang, Wang Lianqing, Yin Qingqing, Hu Wei, Lou Yunwei, Du Jianxin, Zhao Peiqing
Center of Translational Medicine, Zibo Central Hospital Affiliated to Binzhou Medical University, Zibo, China.
Shandong First Medical University, Jinan, China.
Elife. 2024 Dec 27;13:RP92741. doi: 10.7554/eLife.92741.
TIPE () has been identified as an oncogene and participates in tumor biology. However, how its role in the metabolism of tumor cells during melanoma development remains unclear. Here, we demonstrated that TIPE promoted glycolysis by interacting with pyruvate kinase M2 (PKM2) in melanoma. We found that TIPE-induced PKM2 dimerization, thereby facilitating its translocation from the cytoplasm to the nucleus. TIPE-mediated PKM2 dimerization consequently promoted HIF-1α activation and glycolysis, which contributed to melanoma progression and increased its stemness features. Notably, TIPE specifically phosphorylated PKM2 at Ser 37 in an extracellular signal-regulated kinase (ERK)-dependent manner. Consistently, the expression of TIPE was positively correlated with the levels of PKM2 Ser37 phosphorylation and cancer stem cell (CSC) markers in melanoma tissues from clinical samples and tumor bearing mice. In summary, our findings indicate that the TIPE/PKM2/HIF-1α signaling pathway plays a pivotal role in promoting CSC properties by facilitating the glycolysis, which would provide a promising therapeutic target for melanoma intervention.
TIPE（）已被鉴定为一种癌基因，并参与肿瘤生物学过程。然而，其在黑色素瘤发生发展过程中对肿瘤细胞代谢的作用仍不清楚。在此，我们证明TIPE通过与黑色素瘤中的丙酮酸激酶M2（PKM2）相互作用促进糖酵解。我们发现TIPE诱导PKM2二聚化，从而促进其从细胞质向细胞核的转位。TIPE介导的PKM2二聚化进而促进HIF-1α激活和糖酵解，这有助于黑色素瘤进展并增加其干性特征。值得注意的是，TIPE以细胞外信号调节激酶（ERK）依赖的方式特异性地在Ser 37位点磷酸化PKM2。同样，在临床样本和荷瘤小鼠的黑色素瘤组织中，TIPE的表达与PKM2 Ser37磷酸化水平和癌症干细胞（CSC）标志物呈正相关。总之，我们的研究结果表明，TIPE/PKM2/HIF-1α信号通路通过促进糖酵解在促进CSC特性方面起关键作用，这将为黑色素瘤干预提供一个有前景的治疗靶点。
