Stomatin-Mediated Inhibition of the Akt Signaling Axis Suppresses Tumor Growth

Abstract

The growth and progression of cancers are crucially regulated by the tumor microenvironment where tumor cells and stromal cells are mutually associated. In this study, we found that stomatin expression was markedly upregulated by the interaction between prostate cancer cells and stromal cells. Stomatin suppressed cancer cell proliferation and enhanced apoptosis in vitro and inhibited xenograft tumor growth in vivo. Stomatin inhibited Akt activation, which is mediated by phosphoinositide-dependent protein kinase 1 (PDPK1). PDPK1 protein stability was maintained by its binding to HSP90. Stomatin interacted with PDPK1 and interfered with the PDPK1–HSP90 complex formation, resulting in decreased PDPK1 expression. Knockdown of stomatin in cancer cells elevated Akt activation and promoted cell increase by promoting the interaction between PDPK1 and HSP90. Clinically, stomatin expression levels were significantly decreased in human prostate cancer samples with high Gleason scores, and lower expression of stomatin was associated with higher recurrence of prostate cancer after the operation. Collectively, these findings demonstrate the tumor-suppressive effect of stromal-induced stomatin on cancer cells. Significance: These findings reveal that interactions with stromal cells induce expression of stomatin in prostate cancer cells, which suppresses tumor growth via attenuation of the Akt signaling axis.

Cell‐to‐cell contact‐mediated regulation of tumor behavior in the tumor microenvironment

“…We have determined the functions of these proteins in cancer cells, particularly in prostate cancer cells. 9 , 10 In this section, we introduce their detailed roles in cancer biology.…”

“… 10 Induction of stomatin expression in LNCaP and PC3M cells, both of which do not express endogenous stomatin in the normal condition, strongly suppresses cell proliferation and induces apoptosis, leading to the inhibition of tumor growth. 10 Stomatin‐mediated tumor suppression is caused by the inhibition of the Akt signaling pathway, which is crucial for cell proliferation and survival. 34 Akt activation is mainly induced by phosphoinositide‐dependent protein kinase 1 (PDPK1), and the stability of PDPK1 is maintained by its binding to heat shock protein 90 (HSP90).…”

“…Conversely, loss of function of stomatin in prostate cancer 22Rv1 cells, which express a certain degree of stomatin endogenously on the plasma membrane, elevates Akt activation and enhances tumor growth. 10 Clinically, stomatin levels are significantly decreased in human prostate cancers with high Gleason scores, and lower levels of stomatin are associated with increased recurrence of prostate cancer after surgery. 10 These findings demonstrate the tumor‐suppressive effect of stomatin on cancer cells (Figure 2B ).…”

“… 10 Clinically, stomatin levels are significantly decreased in human prostate cancers with high Gleason scores, and lower levels of stomatin are associated with increased recurrence of prostate cancer after surgery. 10 These findings demonstrate the tumor‐suppressive effect of stomatin on cancer cells (Figure 2B ).…”

“…We identified 30 genes that were markedly upregulated in cocultured LNCaP cells, including epithelial membrane protein 1 (EMP1) and stomatin, which are associated with the plasma membrane. We have determined the functions of these proteins in cancer cells, particularly in prostate cancer cells 9,10 . In this section, we introduce their detailed roles in cancer biology.…”