Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

Abstract

Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007).

A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer

“…2E , middle). Likewise, the expression of GCLC, a gene notorious for driving chemoresistance in several cancers 41 – 43 , was only significantly downregulated by a combination of curcumin and OPCs (p = 0.005 for SW480 cells), not individually (Fig. 2E , middle).…”

A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations

“…Thioredoxin is encoded by the gene TXN , and reduced thioredoxin is regenerated by thioredoxin reductase, which is encoded by TXNRD1 . Moreover, the NRF2 cancer targets TKT (encodes transketolase) and ME1 (encodes malic enzyme 1) are important for generation of the reducing agent NADPH that are also key regulators of oncogenic metabolic reprogramming [110] , [111] , [112] , and the metabolic enzymes and transporters encoded by ABCB6 , ABCC3 , AKR1C3 , EPHX1 , GSTM3 , and NQO1 have been implicated in chemoresistance and/or radiation resistance [70] , [113] , [114] , [115] , [116] , [117] . In addition, multiple NRF2 cancer targets have cell cycle-related functions that could contribute to NRF2's oncogenic potential.…”

A highly selective fluorescent probe for human NAD(P)H:quinone oxidoreductase 1 (hNQO1) detection and imaging in living tumor cells

“…hNQO1 is expressed 2-50 times more in cancer cells than in normal cells, so hNQO1 can be used as a biomarker for cancer diagnosis, which is signicant for the early diagnosis of cancer. [18][19][20][21][22] 2-Dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF) has three conjugated systems of strong electronwithdrawing cyano and its derivative TCF-OH contains a donor-p-acceptor (D-p-A) structure, which is widely used to construct novel near-infrared uorescent probes and non-linear optic chromophores and avoid autouorescence interference by tissue. [23][24][25][26][27] Recently, a variety of uorescent probes for biological imaging have been reported based on TCF structures.…”