Journal Article

GANT61 suppresses proliferation and induces apoptosis in ALK-Positive anaplastic large cell lymphoma via modulating the Hh-PIK3IP1-Akt signaling axis

Zhu, Xiongpeng, Chen, Hongyuan, Gao, Jingjing, Liu, Shengquan, Li, Chuntuan, Han, Yan

2026

Overview

This study aimed to initially characterize the effects of GANT61, a Hedgehog (Hh) signaling pathway inhibitor, on the biological behaviors of ALK-positive anaplastic large cell lymphoma (ALK + ALCL) cell lines and explore its underlying mechanisms. Cell proliferation was determined by CCK-8 assays. Cell cycle distribution and apoptotic rates were assessed by flow cytometry. Differential gene analysis and pathway enrichment studies were conducted using datasets from the GEO database with R packages. Protein expression levels of apoptosis-related markers (Bcl-2, Bax, caspase-3, cleaved caspase-3) and signaling molecules (Gli1, PIK3IP1, Akt, phosphorylated Akt) were quantitatively examined by western blotting. Corresponding mRNA levels were quantified by qRT-PCR. GANT61 treatment inhibited proliferation in a dose- and time-dependent manner, induced cell cycle arrest, and promoted apoptosis in ALK + ALCL cell lines. Notably, PIK3IP1 expression was markedly reduced compared with normal lymphocyte controls, while GAS1 expression showed significant upregulation in ALK + ALCL cell lines. Gene Set Enrichment Analysis (GSEA) demonstrated significant enrichment of the PI3K/Akt and Hh signaling pathways. Mechanistically, GANT61 upregulated PIK3IP1 while downregulating both Gli1 protein level and Akt phosphorylation. The Gli-targeting agent GANT61 may inhibit ALK + ALCL cell growth, trigger cell cycle arrest and induce apoptosis through Gli1 inhibition, potentially leading to PIK3IP1 upregulation and subsequent attenuation of PI3K/Akt pathway activity. These findings indicate that the Hh-PIK3IP1-Akt signaling axis may participate in ALK + ALCL tumorigenesis, showing that conventional target drugs can be employed for ALK + ALCL treatment.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V,Springer
• Subject: ALK-positive anaplastic large cell lymphoma / Anaplastic Lymphoma Kinase - metabolism / Antibodies / Apoptosis / Apoptosis - drug effects / Cell cycle / Cell Line, Tumor / Cell Proliferation - drug effects / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Hedgehog pathway / Hedgehog Proteins - metabolism / Hematology / Humans / Lymphoma / Lymphoma, Large-Cell, Anaplastic - drug therapy / Lymphoma, Large-Cell, Anaplastic - genetics / Lymphoma, Large-Cell, Anaplastic - metabolism / Lymphoma, Large-Cell, Anaplastic - pathology / Medical prognosis / Medicine / Medicine & Public Health / Oncology / Phosphatase / PI3K/Akt pathway / Protease inhibitors / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Pyridines - pharmacology / Pyrimidines - pharmacology / Signal Transduction - drug effects / Targeted therapy