Abstract
Emerging evidence implicates serine/threonine kinase 32C (STK32C) overexpressed in bladder cancer and brain tissues acts as a molecular target for doxorubicin resistance, yet its role in colorectal cancer (CRC) remains unclear. Thus. this study investigates the oncogenic mechanism of STK32C in CRC and its interplay with HSP90 and the PI3K/AKT/mTOR signaling axis. STK32C was markedly upregulated in CRC cell lines (HCT116, HT29, SW480, SW620) compared to normal fibroblasts (CCD-18Co) with poor prognosis. STK32C depletion suppressed proliferation, migration, and invasion, while promoting apoptosis-as evidenced by increased Bax, Annexin V, TUNEL-positive, and sub-G1 populations, alongside reduced Bcl-2, pro-Caspase-3, and pro-PARP. Mechanistically, STK32C directly bound the N-terminal domain of HSP90, as shown by immunoprecipitation, immunofluorescence, and GST pulldown assays. Consistently, STK32C depletion or HSP90 N-terminal inhibitor Ganetespib reduced STK32C and p-AKT1, while the HSP90 C-terminal inhibitor, epigallocatechin gallate (EGCG) or AKT inhibitor LY294002 did not affect STK32C, implying that STK32C acts as an upstream of AKT. Furthermore, STK32C depletion enhanced 5-fluorouracil (5-FU) efficacy, with synergistic effects confirmed by CompuSyn and SynergyFinder analysis. In vivo, STK32C depletion reduced the growth of HCT116 cells in BALB/c mice with decreased expression of STK32C, HSP90, PCNA, and AKT and activated caspase 3. Overall, these findings suggest STK32C as a novel oncogenic driver in CRC that modulates HSP90 and PI3K/AKT/mTOR signaling and highlights its potential as a therapeutic target alone or in combination with 5-FU.