SQSTM1/p62 drives radiosensitivity in cervical cancer via autophagy-independent mechanisms

Cervical cancer comprises squamous cell carcinomas (SCCs), which are generally radiosensitive; meanwhile, adenocarcinomas respond poorly to radiation. Here, we explored the role of selective autophagy receptors in modulating radiosensitivity across these subtypes. We found that SQSTM1/p62 was highly expressed in human papillomavirus (HPV)-positive SCC cell lines (HeLa, ME180) and clinical SCC specimens, but was low or undetectable in HPV-negative adenocarcinomas and the C33A cell line. Clonogenic assays confirmed that HPV-positive cells exhibited greater radiosensitivity than C33A. Upon irradiation, only HPV-positive cells showed upregulation of p62 and DNA-damage response proteins, whereas C33A cells did not. Treatment with autophagy inhibitors (bafilomycin A1 and chloroquine) further increased p62 levels in HPV-positive cells but not in HPV-negative cells. The sustained low p62 levels in C33A cells, regardless of autophagy inhibition, may represent a distinctive biomolecular feature of HPV-negative cervical cancer. Notably, overexpression of Atg4B to block autophagic flux without affecting p62 expression had no impact on radiosensitivity in either cell type, whereas pharmacologic inhibition of autophagy selectively enhanced radiation-induced cytotoxicity in HPV-positive cells. Conversely, siRNA-mediated knockdown of p62 in HPV-positive cells attenuated radiation-induced growth suppression. Together, these data indicate that p62 promotes radiosensitivity in HPV-positive cervical cancer through a mechanism distinct from classical autophagy. Therefore, p62 represents both a predictive biomarker for radiation response and a potential target for radiosensitization strategies in HPV-positive tumors, while its unresponsiveness in HPV-negative cancers suggests the need for alternative approaches in that context.