Abstract
The transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow-derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects. SIGNIFICANCE: This study clarifies the importance of Nrf2 activation in the tumor microenvironment and in the host for the suppression of malignant Nrf2-activated cancers and proposes new cancer therapies utilizing inducers of Nrf2.
Highlights
The adaptive responses of cancer cells to their microenvironments are critical for tumor progression
To assess whether Nrf2 activation in the host microenvironment affects the progression of Nrf2-activated tumors, we used two unique types of Keap1-flox mouse lines harboring the Keap1FA [39, 40] or Keap1FB [38] alleles (Fig. 1A)
We examined the tumor-suppressive effects of Nrf2-charged microenvironments, especially on Nrf2-activated tumors, by examining two types of Keap1-flox mice, which have very unique features when combined
Summary
The adaptive responses of cancer cells to their microenvironments are critical for tumor progression. Cancer cells acquire several adaptive systems to respond to their microenvironment, such as hypoxic, oxidative, undernutrition, and acidic conditions, in addition to host immunity [1,2,3,4]. The Keap (Kelch-like ECH-associated protein 1)-Nrf (NF-E2-related factor 2) pathway is frequently activated in cancer cells [5]. The activation of the Keap1– Nrf pathway protects cancer cells from the oxidative microenvironment and provides survival and proliferative benefits or malignancy to cancer cells [6, 7]. The transcription factor Nrf is a master regulator of the cellular response to oxidative stress [8, 9].
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