Abstract
The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.
Highlights
Escaping anoikis, a form of programmed cell death, is critical for cancer cell survival after detaching from the extracellular matrix (ECM)
A western blot analysis was performed on the prostate cancer (PCa) cells in suspension culture at different times to further investigate the autophagic impact on the anoikis resistance process
The results showed that the LC3BII/ LC3BI ratio and p-Beclin1 level increased within 8 h, reaching a peak at 72 h (Fig. 1E), and were distinctly higher after Rapa treatment (200 nM) for 24 h
Summary
A form of programmed cell death, is critical for cancer cell survival after detaching from the extracellular matrix (ECM). Anoikis resistance ensures the survival of aggressive cells in the circulatory system and is deemed essential for cancer progression [1]. Various studies have revealed that cancer cells utilize multi-faceted mechanisms to evade anoikis [1, 2], the precise molecular mechanisms involved in prostate cell survival following ECM detachment remains unclear. The exact role of autophagy in prostate cancer (PCa) cell survival in nonadherent conditions and whether autophagy is linked with anoikis resistance remain unclear. Previous studies have suggested that the disruption of anoikis resistance and autophagy might serve as a therapeutic strategy for advanced PCa [8, 9]. Few molecular targets link protective autophagy with anoikis resistance in PCa cells. The results reveal that cell migration-inducing protein (CEMIP), known as KIAA1199, is significantly overexpressed in PCa-AR cells, promoting tumor metastasis via metabolic reprogramming [12]
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