SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization

Abstract

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 (O 2 < 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.

Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation

“…SPINK1 is identified as a plasma marker for radiation resistance in cancer cells, upregulated by radiation-induced hypoxia. 70 Reports also suggest that the expression of SPINK1 is modulated by androgen receptor (AR) and repressor element-1 silencing transcription factor, a corepressor of AR, 71 indicating that this gene can be differentially regulated in males and females. Among the PBI-treated NHPs, SMAD1 gene expression was higher in males at day 4 post exposure but decreased at day 7 ( Figure S9 ).…”

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

“…382,383 The serine peptidase inhibitor Kazal type 1 (SPINK1) is secreted in a HIF-dependent paracrine manner to reduce radiation-induced DNA damage and enhance radiation resistance in adjacent cancer cells through EGFR and nuclear factor erythroid 2-related factor 2 (NRF2). 384 Radiation-induced EC death leads to secondary tumor cell killing. 385 The vascular system also affects radiation therapy.…”

SPINKs in Tumors: Potential Therapeutic Targets

“…Hypoxia causes an increase in secreted SPINK1 levels in a hypoxia-inducible factor-1 (HIF-1)-dependent manner. SPINK1 protein was detected in and around the hypoxic area of tumor tissue, and it increased with decreasing oxygen supply (61). Even under normoxic conditions, secreted SPINK1 protein enhances the radiation tolerance of cancer cells in a manner dependent on epidermal growth factor receptor (EGFR) and nuclear factor erythroid 2 related factor 2 (NRF2) and accelerates the growth of tumors after radiotherapy.…”

“…Even under normoxic conditions, secreted SPINK1 protein enhances the radiation tolerance of cancer cells in a manner dependent on epidermal growth factor receptor (EGFR) and nuclear factor erythroid 2 related factor 2 (NRF2) and accelerates the growth of tumors after radiotherapy. SPINK1 secreted by hypoxic cells protects surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner (61).…”