Microenvironmental Activation of Nrf2 Restricts the Progression of Nrf2-Activated Malignant Tumors

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.

The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment

“…We surmised that KEAP1 expression levels in the microenvironment might affect tumor progression through NRF2 activation. To verify this notion, we exploited the Kras G12D -driven lung adenocarcinoma system [ 96 ] and examined two mouse models with different NRF2 activity levels in the presence of adenovirus expressing Cre recombinase [ 97 ]: KEAP1 flox-A mice [ 17 ] and KEAP1 flox-B mice [ 98 ]. The KEAP1 flox-A mice exhibit generalized hypomorphic KEAP1 knockdown and therefore show both general NRF2 activation and additional tumor-specific NRF2 activation induced by Cre recombinase, while the KEAP1 flox-B mice do not have this hypomorphic trait and show only Cre-mediated tumor-specific NRF2 activation.…”

“…Importantly, in KEAP1 flox-A : Cre mice, NRF2 activation in bone marrow-derived host immune cells leads to tumor suppression [ 97 ]. NRF2-inducers seem to be effective in the microenvironment, and this observation may indicate its therapeutic potential, especially in combination with NRF2 inhibitors or other strong anticancer drugs.…”

<p>Acacetin Alleviates Inflammation and Matrix Degradation in Nucleus Pulposus Cells and Ameliorates Intervertebral Disc Degeneration in vivo</p>

“…38 Nrf2 activity is controlled by Keap1 in a stress-dependent manner, and once Nrf2 is activated following various stimuli, it detaches from Keap1, translocates into the nucleus, and then binds to the antioxidant response element (ARE), initiating the synthesis of antioxidant proteins including NQO1, HO-1, SOD, glutamate cysteine ligase catalytic subunit (GCLC), and glutathione-S-transferases (GST). [39][40][41] We treated NPCs with acacetin and analyzed the intranuclear content of the Nrf2 protein, demonstrating that acacetin also activated the Nrf2 pathway in NPCs. The downstream protein expression levels of NQO1, HO-1 and SOD were also dramatically upregulated.…”

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

“…The regulation of the immune microenvironment also extends beyond macrophages to other myeloid populations and regulatory T cells [ 112 , 113 ], which can influence tumor progression and metastasis. Importantly, NRF2 activation within the tumor microenvironment suppressed the progression of mutant Kras -driven lung tumors [ 114 ]. It is not surprising that immune populations can direct their own function through NRF2 regulation.…”