PHA-665752's Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells

• Published in: International journal of molecular sciences 2024-03, Vol.25 (5), p.2871
• Main Authors: Yadav, Anil Kumar, Wang, Saini, Shin, Young-Min, Jang, Byeong-Churl
• Format: Article
• Language: English
• Subjects: Apoptosis; c-Met; Cancer cells; Cancer therapies; Carcinoma, Squamous Cell - metabolism; Cell growth; Cell Line, Tumor; Gastric cancer; Genetic transcription; Growth factors; HIF-1α; HSC-3; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Kinases; Ligands; Mcl-1; Metastasis; Mouth cancer; Mouth Neoplasms - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Oncology; Oral cancer; PHA-665752; Phosphorylation; Protein kinases; Proteins; Software; Squamous cell carcinoma; Src; Sulfones; Tumors; Tyrosine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25052871

c-Met is a tyrosine-kinase receptor, and its aberrant activation plays critical roles in tumorigenesis, invasion, and metastatic spread in many human tumors. PHA-665752 (PHA) is an inhibitor of c-Met and has antitumor effects on many hematological malignancies and solid cancers. However, the activation and expression of c-Met and its role and the antitumor effect of PHA on human oral squamous cell carcinoma (OSCC) cells remain unclear. Here, we investigated the activation and expression of c-Met and the effects of PHA on the growth of a highly tumorigenic HSC-3 human OSCC cell line with high c-Met phosphorylation and expression. Of note, c-Met was highly expressed and phosphorylated on Y1234/1235 in HSC-3 cells, and PHA treatment significantly suppressed the growth and induced apoptosis of these cells. Moreover, PHA that inhibited the phosphorylation (activation) of c-Met further caused the reduced phosphorylation and expression levels of Src, protein kinase B (PKB), mammalian target of rapamycin (mTtor), and myeloid cell leukemia-1 (Mcl-1) in HSC-3 cells. In addition, the antiangiogenic property of PHA in HSC-3 cells was shown, as evidenced by the drug's suppressive effect on the expression of hypoxia-inducible factor-1α (HIF-1α), a critical tumor angiogenic transcription factor. Importantly, genetic ablation of c-Met caused the reduced growth of HSC-3 cells and decreased Src phosphorylation and HIF-1α expression. Together, these results demonstrate that c-Met is highly activated in HSC-3 human oral cancer cells, and PHA exhibits strong antigrowth, proapoptotic, and antiangiogenic effects on these cells, which are mediated through regulation of the phosphorylation and expression of multiple targets, including c-Met, Src, PKB, mTOR, Mcl-1, and HIF-1α.