Protein kinase D1 modulates LET- and dose-dependent radiosensitivity in prostate cancer cells

Protein kinase D1 (PrKD1) participates in DNA damage response signaling, but its role in modulating dose- and linear energy transfer (LET)-dependent radiosensitivity in prostate cancer remains poorly defined. We evaluated the effect of PrKD1 loss on clonogenic survival following photon and proton irradiation to determine whether PrKD1 influences radiosensitivity across clinically relevant dose ranges. LNCaP and their PrKD1-knockdown derivative (shPrKD1) prostate cancer cells were exposed to 0-4 Gy X-rays or proton irradiation delivered at increasing dose-averaged LET (PL2-PL4 = 2-4 keV/µm). Clonogenic survival was normalized to unirradiated controls, and linear-quadratic modeling was used to derive D10, D37, and relative biological effectiveness (RBE) values. Both cell lines showed a dose-dependent decline in survival, but their response profiles diverged with dose and LET. LNCaP cells were more radioresistant at 1 Gy and demonstrated a steep loss of viability from 2-4 Gy with LET-associated sensitization that was most evident at PL4 and at higher doses. In contrast, shPrKD1 cells exhibited greater sensitivity at low-to-intermediate doses (≤2 Gy), a more linear survival curve, and reduced LET dependence. The survival curves crossed at higher doses, with shPrKD1 more sensitive at clinically relevant doses yet relatively more resistant at high, near-ablative doses. D10 values ranged from 5.2-5.7 Gy in shPrKD1 versus 4.2-5.1 Gy in LNCaP, with both cell lines showing greatest sensitization at PL4. RBE values remained modest (~1.0-1.2) but increased slightly with LET in shPrKD1, indicating enhanced sensitivity at intermediate doses. These findings demonstrate that PrKD1 loss enhances radiosensitivity in the fractionated dose range and attenuates LET-dependent effects, identifying protein kinase D1 as a modulator of radiation response and a potential biomarker for optimizing proton and photon therapy strategies in prostate cancer.