Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

Abstract

In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription 3 (STAT3) proteins were analyzed by Western blot. The response to ethanol and curcumin seemed to be cell-type specific, with respect to all parameters analyzed. High sensitivity to curcumin was present in the cell lines originating from head and neck squamous cell carcinomas: FaDu, Detroit 562 and, especially, Cal27. Very low sensitivity was observed in the colon adenocarcinoma-originating HT-29 cell line, which retained, after exposure to curcumin, a higher levels of lactate production despite decreased glucose consumption. The effects of ethanol were significant.

Vanillin downregulates NNMT and attenuates NNMT‑related resistance to 5‑fluorouracil via ROS‑induced cell apoptosis in colorectal cancer cells

“…In HT-29 cell lines, no STAT3 phosphorylation was detected by western blot analysis, with or without vanillin treatment. The low phosphorylation of STAT3 in HT-29 cells was also reported previously (32,33). Several other researchers obtained the slight bands of phospho-STAT3 in HT-29 cells (34,35), but we attempted many times and failed to obtain a clear band of phospho-STAT3 in our experiments.…”

Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer

“…101 Curcumin has shown anticancer mechanisms linked to lactate production, including a decline in PKM2 caused by its suppressive activity on the Warburg effect in H157 and H413 head and neck cancer (HNC) cells. Curcumin consumption also diminished the transcription of PKM1 in Cal27 human tongue squamous carcinoma cells, [102][103][104] glyoxalase I (GLO) inhibition in the presence of antimycin A in MCF-7 breast cancer cells, 105 and inhibition of Akt/mTOR signaling pathway as upstream signaling event of lactate. 106 As mentioned above, curcumin possesses inhibitory effects on glucose uptake and lactate production by downregulation of PKM2, via the inhibition of mTOR/HIF1α signaling in various cancer cell lines, for instance, lung (H1299), breast (MCF-7), cervical (HeLa), prostate (PC3), and human embryonic kidney (HEK) cells.…”

“…As mentioned above, curcumin possesses inhibitory effects on glucose uptake and lactate production by downregulation of PKM2, via the inhibition of mTOR/HIF1α signaling in various cancer cell lines, for instance, lung (H1299), breast (MCF‐7), cervical (HeLa), prostate (PC3), and human embryonic kidney (HEK) cells 107 . Additionally, curcumin‐mediated reduction of GLUT1 and HK2 mRNA expression is another mechanism for the inhibition of Warburg effect and, therefore, is associated with decreased survival of cancer cells 103,105,106,108 . Curcumin treatment has also been found to modulate the extracellular milieu of HepG2 cells following augmented lactate level 104 .…”

Implementing Curcumin in Translational Oncology Research

“…Nuclear translocation of PKM2 and its direct interaction with a transcriptional cofactor repressor TGF-β-induced factor homeobox 2 (TGIF2), causes recruitment of histone deacetylase 3 to E-cadherin promoter, leading to EMT through suppression of E-cadherin transcription [ 143 ]. Curcumin has been shown to downregulate the expression of PKM2 [ 144 , 145 ] and to influence its nuclear localization, albeit in a cell-type-specific manner [ 145 ]. In line with curcumin’s negative effect on PKM2 expression and nuclear localization, upregulation of E-cadherin upon curcumin treatment has been reported in various types of cancer cells [ 146 , 147 , 148 , 149 ].…”