Curcumin, but not curcumin-glucuronide, inhibits Smad signaling in TGFβ-dependent bone metastatic breast cancer cells and is enriched in bone compared to other tissues

Abstract

Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e.g., PTHrP) induced by bone matrix-derived growth factors (e.g., TGFβ). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGFβ/Smad-signaling in a TGFβ-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGFβ signaling were compared in a series of BCa cell lines forming TGFβ-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC-MS. While curcumin inhibited TGFβ-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287, and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGFβ-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissuespecific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGFβ-signaling and undergo site specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a pro-drug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols.

Periodic Curcumin Monoglucuronide Injections Ameliorate Structural Osteoarthritis Changes in Rats with Destabilized Medial Meniscus

“…This study indicated that TBP1901 has signi cant bene cial effects on the SB and osteophytes, which were less seen in previous reports of administered curcumin. These remarkable effects for SB and osteophytes may be due to the presence of free curcumin derived from TBP1901 hydrolyzed by one of the many glucuronidases produced in the bone marrow [35,42].…”

“…Ingested curcumin is mostly present as molecular conjugates in the body, with almost no free-form curcumin, which is most important for pharmacological activity [33][34][35]. The in vitro pharmacological activity of curcumin (e.g., anticancer effects) is associated with the free-form curcumin, not curcumin monoglucuronide (TBP1901), which is the major metabolite in serum [36,37].…”

“…Due to this enzyme, the intravenous administration of synthesized TBP1901 in mice showed the presence of freeform curcumin in the blood at a constant level (approximately 4-16% of total curcumin levels), and the tumor growth was signi cantly suppressed [42]. Furthermore, the bone has been shown to contain more aglycone curcumin and curcumin than other tissues when curcumin is ingested, probably because the βglucuronidase expressed in bone marrow cells deconjugates TBP1901 [35,43]. Previous studies on bone diseases using curcumin have reported that the deglucuronidation activity of bone marrow cells has given bone protective effects, despite curcumin having low bioavailability [44,45].…”

Curcumin inhibited the growth and invasion of human monocytic leukaemia SHI-1 cellsin vivoby altering MAPK and MMP signalling

“…Moreover, curcumin inhibits liver metastasis of gastric cancer by reducing circulating tumour cells (Gu et al 2019). Curcumin inhibited SMADs signalling in TGF-b-dependent breast cancer cells metastasized to bone (Kunihiro et al 2019). Curcumin attenuated hyperglycemia-driven EGF-induced invasive and migratory pancreatic cancer cells via suppression of the ERK and AKT pathways (Li et al 2019).…”

Curcumin mitigates the epithelial‐to‐mesenchymal transition in biliary epithelial cells through upregulating CD109 expression

“…Curcumin is a natural polyphenolic compound extracted from the Curcuma longa and has multiple biological properties (Bahramsoltani, Rahimi, & Farzaei, 2017;Kumar, Mittal, Sak, & Tuli, 2016). Moreover, curcumin can attenuate the TGF-β1-induced EMT in breast cancer cells, intestinal fibroblasts, and others via inhibiting the Smad, peroxisome proliferator-activated receptorγ (PPARγ), and mechanistic target of rapamycin (mTOR) signaling (Kunihiro et al, 2019;Xu et al, 2017;Zhu et al, 2017). However, whether curcumin could modulate the TGF-β1-induced EMT in BECs and its potential mechanisms has not been clarified.…”