TY - JOUR AU - Suwa, Tatsuya AU - Kobayashi, Minoru AU - Shirai, Yukari AU - Nam, Jin-Min AU - Tabuchi, Yoshiaki AU - Takeda, Norihiko AU - Akamatsu, Shusuke AU - Ogawa, Osamu AU - Mizowaki, Takashi AU - Hammond, Ester M. AU - Harada, Hiroshi T1 - SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization PY - 2021/11/08/ AB - Hypoxia is associated with tumor radioresistance; therefore, a predictive marker for tumor hypoxia and a rational target to overcome it have been sought to realize personalized radiotherapy. Here, we show that serine protease inhibitor Kazal type I (SPINK1) meets these 2 criteria. SPINK1 expression was induced upon hypoxia (O2 < 0.1%) at the transcription initiation level in a HIF-dependent manner, causing an increase in secreted SPINK1 levels. SPINK1 proteins were detected both within and around hypoxic regions of xenografted and clinical tumor tissues, and their plasma levels increased in response to decreased oxygen supply to xenografts. Secreted SPINK1 proteins enhanced radioresistance of cancer cells even under normoxic conditions in EGFR-dependent and nuclear factor erythroid 2–related factor 2–dependent (Nrf2-dependent) manners and accelerated tumor growth after radiotherapy. An anti-SPINK1 neutralizing antibody exhibited a radiosensitizing effect. These results suggest that SPINK1 secreted from hypoxic cells protects the surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner, justifying the use of SPINK1 as a target for radiosensitization and a plasma marker for predicting tumor hypoxia. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.148135 VL - 6 IS - 21 UR - https://doi.org/10.1172/jci.insight.148135 PB - The American Society for Clinical Investigation ER -