Abstract
The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc–curcumin Zn(II)–curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)–curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)–curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies.
Highlights
Nuclear factor erythroid 2 p45-related factor 2 (NRF2) is the master regulator of oxidative stress and is often upregulated in solid cancers, promoting proliferation and resistance to chemotherapy and to apoptosis [1,2]
In canonical NRF2 activation, which is under oxidative or electrophilic stress, the Kelch-likeECH-associated protein 1 (Keap1) ubiquitine ligase activity declines, leading to the stabilization of NRF2 that subsequently translocates to the nucleus where it induces the transcription of antioxidant response element (ARE)-bearing target genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase (NQO1)
We recently found that NRF2 activation, by a novel ruthenium(II)–curcumin compound, plays a pro-survival role in both wild-type p53- and mutant p53-carrying cancer cells balancing cell death/survival; inhibiting the NRF2 survival pathway could increase cancer cell death [12,13]
Summary
Nuclear factor erythroid 2 p45-related factor 2 (NRF2) is the master regulator of oxidative stress and is often upregulated in solid cancers, promoting proliferation and resistance to chemotherapy and to apoptosis [1,2]. NRF2 is continuously inactivated by ubiquitin-proteasome degradation following its interaction with Kelch-like. ECH-associated protein 1 (Keap1)-associated E3 ubiquitine ligase [3]. In canonical NRF2 activation, which is under oxidative or electrophilic stress, the Keap ubiquitine ligase activity declines, leading to the stabilization of NRF2 that subsequently translocates to the nucleus where it induces the transcription of antioxidant response element (ARE)-bearing target genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase (NQO1). In non-canonical NRF2 activation, p62/sequestome 1 (SQSTM1, hereafter referred as p62), a key autophagyc adaptor, interacts with Keap, inducing its degradation through autophagy, thereby triggering NRF2 stabilization and activation [4]. NRF2 can induce p62 transcription by binding antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress
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