Luteolin sensitizes the antiproliferative effect of interferon α/β by activation of Janus kinase/signal transducer and activator of transcription pathway signaling through protein kinase A-mediated inhibition of protein tyrosine phosphatase SHP-2 in cancer cells

Organic solvent–luteolin interactions studied by FT-Raman, Vis-Raman, UV-Raman spectroscopy and DFT calculations

“…Luteolin's most outstanding biological properties are its antioxidant ( [5] and refs. therein), antiinflammatory [4] and anti-tumor activities ( [6] and refs. therein).…”

Emodin potentiates the antiproliferative effect of interferon α/β by activation of JAK/STAT pathway signaling through inhibition of the 26S proteasome

“…We previously found that luteolin, a natural flavonoid, enhances the antiproliferative effect of IFN-α/β on cancer cells by augmenting the activation of JAK/STAT signaling. Such potentiation is achieved via decreases in intracellular cAMP levels through activation of IFNAR2-bound phosphodiesterase activity and subsequent PKA-stimualted tyrosine phosphatase SHP-2 inhibition [ 3 ], which is quite different from the mechanism of emodin reported here. The proteasome also participates in the internalization and degradation of other cell membrane-bound cytokine receptors such as the growth hormone receptor, interleukin-2 receptor, or epidermal growth factor receptor [ 46 – 48 ].…”

“…Total RNA was extracted with TRIzol reagents (Invitrogen) and cDNA was generated using SuperScript III Reverse Transcriptase (Invitrogen) with oligo dT 18 primer. PKR and 2′5′-OAS1 mRNA was quantified as previously described [ 3 ]. The samples were run in triplicate and the relative expression levels of PKR and 2′5′-OAS1 were determined by normalizing the expression of each target to that of GAPDH using the 2 −ΔΔCt method.…”

“…Therefore, small-molecule activators of JAK/STAT signaling, which could amplify the effects of type I IFNs, are high-priority targets of drug development efforts. Intriguingly, several small-molecular activators of type I IFNs have been identified through cell-based screening and exhibit antiviral or anti-cancerous effects through various mechanisms, including suppression of cAMP-PKA-SHP2 signaling, inhibition of pyrimidine biosynthesis, and activation of type I IFN receptors [ 3 – 5 ]. JAK/STAT signaling pathway stimulated by type I IFNs is regulated in a complex and tissue-specific manner; therefore, new activators of JAK/STAT pathway will facilitate the development of new strategies for IFN therapy [ 6 ].…”

The Natural cAMP Elevating Compound Forskolin in Cancer Therapy: Is It Time?

“…cAMP, either via a PKA‐dependent or PKA‐independent manner, affects numerous cellular functions such as metabolism, gene expression, ion channel activation, cell proliferation, differentiation, apoptosis, and is considered very relevant to cancer (Beavo and Brunton, ; Gancedo, ). Moreover, the cAMP signaling interacts with other intracellular signaling pathways, including cytokine and Ras‐Raf‐ Erk pathways (Follin‐Arbelet et al, ; Spina et al, ; Tai et al, ; Cheng et al, ; Park and Juhnn, ). Notably, these signaling connections also play an important role in cancer biology and a combined blockade of such signaling pathways is considered a relevant strategy for therapeutic intervention to fight cancer (Awada and Aftimos, ; Indovina et al, ; Kidger and Keyse, ).…”