The interaction of Hemin and Sestrin2 modulates oxidative stress and colon tumor growth

Abstract

Several large epidemiological and animal studies demonstrate a direct correlation between dietary heme iron intake and/or systemic iron levels and cancer risk in several cancers including colorectal cancer (CRC). However, the precise mechanisms for how heme iron contributes to CRC and how cancer cells respond to heme iron-induced stress are still unclear. Previously we have shown that one of the stress-inducible proteins, Sestrin2 (SESN2), is a novel tumor suppressor in colon by limiting endoplasmic reticulum stress and mammalian target of rapamycin complex 1 (mTORC1) signaling and tumor growth. But the relationship between heme iron and SESN2, especially in the context of colon carcinogenesis, was not investigated previously. Here, we found that hemin dosedependently increased SESN2 expression in an oxidative stress and nuclear factor (erythroidderived 2)-like 2 (NFE2L2, NRF2)-dependent manner. Since SESN2 overexpression reduced hemin-induced oxidative stress, SESN2 could be an important target of NRF2 exerting antioxidant function. Indeed, expression of several oxidative stress responsive proteins such as NRF2 and its target genes was reduced by SESN2. Although we formerly reported that SESN2 expression was reduced after p53 mutation in colon tumors, mouse colon tumors, which have intact p53 and NRF2, induced SESN2 expression in response to iron stimulus. Although SESN2 overexpression decreased murine colon tumor cell growth both in vitro and in vivo, it rendered colon cancer cells more resistant to hemin-induced apoptosis and therefore promoted tumor growth during hemin treatment. Taken together, although SESN2 generally suppresses tumorigenesis, it can produce tumor-promoting role in iron-rich environment by suppressing oxidative stress-associated cancer cell death.

Heme oxygenase 1 protects human colonocytes against ROS formation, oxidative DNA damage and cytotoxicity induced by heme iron, but not inorganic iron

“…Similarly, treatment of the hepatic cell line HH4 with ferric ammonium citrate resulted in signifcantly increased ROS levels only at concentrations above 1000 µM, while incubation of cells with 100 µM ferric ammonium citrate or ferric chloride did not augment basal ROS levels 31,32 . In support of our results, another study also reported ROS generation in HCT116 and RKO cells treated with 100 µM hemin 33 . Furthermore, we showed that hemin, in contrast to inorganic iron, caused DNA strand breaks as well as oxidative DNA damage (i.e., 8-oxoG) in HCEC and CRC cells.…”

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…The gene expression of Sesn2 upregulated by miR182-5p suppression in arsenic treatment functions as an antioxidant in Uppsala 87 malignant glioma (U87MG), human lung adenocarcinoma H1299, and A549 cell lines (Lin et al, 2018). Sesn2 would promote colorectal cancer cell growth in the iron-rich environment by suppressing ROS (Kim et al, 2019). Sestrins promote anchorage-independent (anoikis resistance) growth of human endometrial cancer cells (Kozak et al, 2019).…”

mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer

“…Our data thus suggest that these correlations between SESN2 and cell cycle-associated genes are independent of the role of CDKN1A and CDKN1B as tumor suppressors in the tumor of patients with endometrial cancer. SESN2 suppresses migration and proliferation in vitro, and tumor growth in vivo in colorectal cancer [27,[55][56][57]. However, the relationship between growth and SESN2 expression has remained unanswered in endometrial cancer.…”

“…SESN2 suppresses migration and proliferation in vitro, and tumor growth in vivo in colorectal cancer [ 27 , 55 , 56 , 57 ]. However, the relationship between growth and SESN2 expression has remained unanswered in endometrial cancer.…”