Nano-Diamino-Tetrac (NDAT) Enhances Resveratrol-Induced Antiproliferation by Action on the RRM2 Pathway in Colorectal Cancers

Abstract

Cancer resistance to chemotherapeutic agents is a major issue in the management of cancer patients. Overexpression of the ribonucleotide reductase regulatory subunit M2 (RRM2) has been associated with aggressive cancer behavior and chemoresistance. Nano-diamino-tetrac (NDAT) is a nanoparticulate derivative of tetraiodothyroacetic acid (tetrac), which exerts anticancer properties via several mechanisms and downregulates RRM2 gene expression in cancer cells. Resveratrol is a stilbenoid phytoalexin which binds to a specific site on the cell surface integrin αvβ3 to trigger cancer cell death via nuclear translocation of COX-2. Here we report that resveratrol paradoxically activates RRM2 gene expression and protein translation in colon cancer cells. This unanticipated effect inhibits resveratrol-induced COX-2 nuclear accumulation. RRM2 downregulation, whether achieved by RNA interference or treatment with NDAT, enhanced resveratrol-induced COX-2 gene expression and nuclear uptake which is essential to integrin αvβ3-mediated-resveratrol-induced antiproliferation in cancer cells. Elsewhere, NDAT downregulated resveratrol-induced RRM2 expression in vivo but potentiated the anticancer effect of the stilbene. These findings suggest that RRM2 appears as a cancer cell defense mechanism which can hinder the anticancer effect of the stilbene via the integrin αvβ3 axis. Furthermore, the antagonistic effect of RRM2 against resveratrol is counteracted by the administration of NDAT.

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer

“…Currently the functional significance of PKMYT1 in prostate cancer remains unclear, and it makes sense to determine whether PKYMT1 is indispensable in prostate cancer, which requires further investigation. The ribonucleotide reductase M2 subunit (RRM2) plays important role in several human cancers, including colorectal cancer, hepatocellular carcinoma, pancreatic adenocarcinoma, and breast cancer (Lee et al, 2014;Sierzega et al, 2017;Nana et al, 2018;Chen et al, 2019). Increased expression of RRM2 has been demonstrated to be a mechanism driving poor patient outcomes in prostate cancer, in accordance with our findings (Mazzu et al, 2019).…”

NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer

“…In addition to EGFR, thyroid hormone (thyroxine, T 4 ) has been shown to be involved in CRC progression [8][9][10][11]. Thyroid hormone can also induce expression/activation of the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoints in different types of cancers [10,12]. PD-L1 expression has a positive correlation with cancer progression and decreased patient survival [13][14][15].…”

“…Gefitinib has been combined with other chemotherapeutic agents to manage a variety of cancers [23][24][25][26]. On the other hand, a deaminated L-thyroxine analog, tetraiodothyroacetic acid (tetrac), and its nanoparticulate analog nano-diamino-tetrac (NDAT) have been shown to inhibit proliferation of cancer cells in vitro and in vivo [8][9][10][27][28][29]. The anticancer properties of NDAT include inhibition of cancer cell proliferation, angiogenesis, metastasis, and immune-escape mechanisms of cancer cells, and it induces apoptosis of cancer cells [27,28,30,31].…”

Herbal Medicines Attenuate PD-L1 Expression to Induce Anti-Proliferation in Obesity-Related Cancers

“…The thyroid hormones, 3,5,3 -triiodo-L-thyronine (T 3 ) and thyroxine, were shown to promote the growth of cancer cells [30,[33][34][35][36]. Recent studies by our group also indicated that thyroxine stimulates the growth of human ovarian and lung cancer cells via the cross-talk between the cell surface αvβ3 integrin receptor and estrogen receptor α (ERα) [37,38].…”

“…Resveratrol can also induce anti-proliferation in various cancer cells [33,34,47] and inhibit cancer growth in vivo [53]. Resveratrol activates ERK1/2 via binding to the receptor on αvβ3 integrin.…”