Photodynamic Therapy as a Potent Radiosensitizer in Head and Neck Squamous Cell Carcinoma

• Published in: Cancers Vol. 13; no. 6; p. 1193
• Main Authors: Cho, Won Jin, Kessel, David, Rakowski, Joseph, Loughery, Brian, Najy, Abdo J, Pham, Tri, Kim, Seongho, Kwon, Yong Tae, Kato, Ikuko, Kim, Harold E, Kim, Hyeong-Reh C
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.03.2021; MDPI
• Subjects: Apoptosis; Autophagy; Cell death; Drug dosages; Endoplasmic reticulum; ER/mitochondrial photosensitizer; Head & neck cancer; Human papillomavirus; Ionizing radiation; Mitochondria; Molecular modelling; paraptosis; Phagocytosis; Photodynamic therapy; Proteins; Radiation therapy; Radioresistance; Risk groups; Squamous cell carcinoma; Statistical analysis; United States > US; apoptosis; autophagy; ER/mitochondrial photosensitizer; paraptosis; photodynamic therapy
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13061193

Despite recent advances in therapeutic modalities such as radiochemotherapy, the long-term prognosis for patients with advanced head and neck squamous cell carcinoma (HNSCC), especially nonviral HNSCC, remains very poor, while survival of patients with human papillomavirus (HPV)-associated HNSCC is greatly improved after radiotherapy. The goal of this study is to develop a mechanism-based treatment protocol for high-risk patients with HPV-negative HNSCC. To achieve our goal, we have investigated molecular mechanisms underlying differential radiation sensitivity between HPV-positive and -negative HNSCC cells. Here, we found that autophagy is associated with radioresistance in HPV-negative HNSCC, whereas apoptosis is associated with radiation sensitive HPV-positive HNSCC. Interestingly, we found that photodynamic therapy (PDT) directed at the endoplasmic reticulum (ER)/mitochondria initially induces paraptosis followed by apoptosis. This led to a substantial increase in radiation responsiveness in HPV-negative HNSCC, while the same PDT treatment had a minimal effect on HPV-positive cells. Here, we provide evidence that the autophagic adaptor p62 mediates signal relay for the induction of apoptosis, promoting ionizing radiation (XRT)-induced cell death in HPV-negative HNSCC. This work proposes that ER/mitochondria-targeted PDT can serve as a radiosensitizer in intrinsically radioresistant HNSCC that exhibits an increased autophagic flux.