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Antitumor effect of sunitinib in human prostate cancer cells functions via autophagy
Bangqi Wang1,2, Dongyuan Lu3, Min Xuan4
1Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Abstract:
The aim of the present study was to explore sunitinib-induced autophagic effects and the specific molecular mechanisms involved, in vitro, using PC-3 and LNCaP human prostate cancer cell lines. Cells were exposed to escalating doses of sunitinib treatment and subsequent cell viability and cell cycle analyses were performed to evaluate the inhibitory effect of sunitinib in vitro. Immunofluorescence staining of microtubule associated protein 1A/1B-light chain 3 (LC3) puncta was employed to assess autophagy levels after sunitinib treatment. Western blot analysis was performed to evaluate variations in the levels of LC3, sequestosome-1, extracellular signal regulated kinase 1/2 (ERK1/2), mammalian target of rapamycin (mTOR), p70 ribosomal protein S6 kinase (p70S6K) and cleaved caspase-3 proteins. The present study revealed that sunitinib treatment inhibited cell growth and triggered autophagy in a dose-dependent manner in both cell lines. In addition, sunitinib activated ERK1/2 and inhibited mTOR/p70S6K signaling. Sunitinib-induced autophagy was notably reversed by ERK1/2 kinase inhibitor, U0126. Furthermore, inhibition of sunitinib-induced autophagy by 3-methyladenine enhanced apoptosis and exhibited improved cell viability, which indicated that sunitinib induces not only apoptosis but also autophagic cell death in prostate cancer cell lines. These results may lead to an improved understanding of the mechanism of sunitinib's cytotoxic action and may provide evidence that combined sunitinib autophagy-regulating treatment may be of benefit to anti-prostate cancer therapy.
Insights
Sunitinib inhibits prostate cancer cell growth and triggers autophagy via ERK1/2 activation and mTOR/p70S6K inhibition. Autophagy modulation combined with sunitinib may enhance anti-cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Prostate cancer remains a significant health concern.
- Sunitinib is an established anti-cancer drug, but its precise mechanisms in prostate cancer require further elucidation.
- Autophagy plays a complex role in cancer progression and treatment response.
Purpose of the Study:
- To investigate the autophagic effects of sunitinib in human prostate cancer cell lines (PC-3 and LNCaP).
- To elucidate the molecular mechanisms underlying sunitinib-induced autophagy.
- To evaluate the potential of combining sunitinib with autophagy-modulating agents for prostate cancer therapy.
Main Methods:
- In vitro treatment of PC-3 and LNCaP cells with sunitinib.
- Cell viability and cell cycle analyses.
- Immunofluorescence staining for LC3 puncta to assess autophagy.
- Western blot analysis for key proteins (LC3, p62, ERK1/2, mTOR, p70S6K, cleaved caspase-3).
Main Results:
- Sunitinib inhibited cell growth and induced autophagy in a dose-dependent manner.
- Sunitinib activated the ERK1/2 pathway and inhibited the mTOR/p70S6K pathway.
- Autophagy induction by sunitinib was reversed by the ERK1/2 inhibitor U0126.
- Inhibition of autophagy enhanced sunitinib-induced apoptosis and cell viability reduction.
Conclusions:
- Sunitinib triggers both apoptosis and autophagic cell death in prostate cancer cells.
- The ERK1/2 and mTOR/p70S6K pathways are key mediators of sunitinib's effects.
- Targeting autophagy in combination with sunitinib may represent a promising strategy for prostate cancer treatment.