Knotwood extract from Norway spruce (Picea abies) as treatment for androgen-independent prostate cancer : In vitro study of insulin signaling and proliferation in PC-3 cells
Ahlnäs, Toveann (2020)
Åbo Akademi
2020
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi-fe202003148200
https://urn.fi/URN:NBN:fi-fe202003148200
Tiivistelmä
Despite advancements in the therapeutic field during the past decades, prostate cancer (PCa) remains one of the most common cancers in men, with a relatively high mortality rate when the disease progresses, and available treatment methods fail. Androgen-independent PCa is an advanced form of the disease due to the cells not relying on androgens anymore for proliferation and survival in comparison to the androgen-dependent prostate cancer cells, which are more responsive to therapy. Instead, androgen-independent PCa cells heavily exploit other growth factors such as insulin and insulin-like growth factor (IGF) for sustained growth. With an increasing incidence worldwide as well as insufficient and costly medication, novel treatment methods are in great demand.
Lignans are polyphenols found throughout the plant kingdom mainly in fiber-rich vegetables and seeds and are known for their many health-promoting properties such as being potent antioxidants, exerting anti-inflammatory features, as well as reducing the risk of cardiovascular diseases. Importantly, lignans show selective toxicity to a variety of cancers including PCa without damaging healthy cells. In this thesis, a knotwood extract from the Norway spruce tree (Picea abies) was studied for its effects on the androgen-independent cell line PC-3 with the main focus on the insulin signaling pathway. Previous studies have investigated the antineoplastic properties of individual lignans, whereas extracts containing a mixture of these compounds have rarely been studied.
Initial analysis of the extract by gas chromatography-mass spectrometry revealed the lignan content to be 31.3%, of which hydroxymatairesinol was the dominant lignan. Live-cell imaging of 48 h treated PC-3 cells in serum-rich medium showed a distinct concentration-dependent suppression of proliferation. Further, the cells arrested in the G0/G1-phase of the cell cycle without apparent cell death as determined by flow cytometry. To identify if the extract targeted insulin-mediated signaling, the cells were treated in serum-free conditions with added insulin for up to 60 min. An evident inhibition of Akt phosphorylation as well as its downstream target Gsk-3b was observed. Expression of p21 was additionally upregulated during a longer treatment time. Surprisingly, however, both pERK and pAkt were stimulated upon lower extract concentrations contradicting proliferation repression and cell cycle arrest. Intriguingly, treatment in growth factor depleted conditions revealed PC-3 cells to be highly sensitized to the extract, initiating necroptosis-like cell death.
The results in this thesis demonstrate the antineoplastic effects of the P. abies knotwood extract on PC-3 cells in vitro. Mechanism of action is tied to altered PI3K/Akt and MAPK signaling, where the amount of available growth factors as well as the cell’s energy metabolism influence the lethal effects, possibly revealing how lignans exert their selectivity to cancer cells in general.
Lignans are polyphenols found throughout the plant kingdom mainly in fiber-rich vegetables and seeds and are known for their many health-promoting properties such as being potent antioxidants, exerting anti-inflammatory features, as well as reducing the risk of cardiovascular diseases. Importantly, lignans show selective toxicity to a variety of cancers including PCa without damaging healthy cells. In this thesis, a knotwood extract from the Norway spruce tree (Picea abies) was studied for its effects on the androgen-independent cell line PC-3 with the main focus on the insulin signaling pathway. Previous studies have investigated the antineoplastic properties of individual lignans, whereas extracts containing a mixture of these compounds have rarely been studied.
Initial analysis of the extract by gas chromatography-mass spectrometry revealed the lignan content to be 31.3%, of which hydroxymatairesinol was the dominant lignan. Live-cell imaging of 48 h treated PC-3 cells in serum-rich medium showed a distinct concentration-dependent suppression of proliferation. Further, the cells arrested in the G0/G1-phase of the cell cycle without apparent cell death as determined by flow cytometry. To identify if the extract targeted insulin-mediated signaling, the cells were treated in serum-free conditions with added insulin for up to 60 min. An evident inhibition of Akt phosphorylation as well as its downstream target Gsk-3b was observed. Expression of p21 was additionally upregulated during a longer treatment time. Surprisingly, however, both pERK and pAkt were stimulated upon lower extract concentrations contradicting proliferation repression and cell cycle arrest. Intriguingly, treatment in growth factor depleted conditions revealed PC-3 cells to be highly sensitized to the extract, initiating necroptosis-like cell death.
The results in this thesis demonstrate the antineoplastic effects of the P. abies knotwood extract on PC-3 cells in vitro. Mechanism of action is tied to altered PI3K/Akt and MAPK signaling, where the amount of available growth factors as well as the cell’s energy metabolism influence the lethal effects, possibly revealing how lignans exert their selectivity to cancer cells in general.