Rictor Activates Cav 1 Through the Akt Signaling Pathway to Inhibit the Apoptosis of Gastric Cancer Cells

Abstract

BackgroundRapamycin-insensitive companion of mammalian target of rapamycin (Rictor) protein is a core subunit of mammalian target of rapamycin complex 2, and is associated with cancer progression. However, the biological function of Rictor in cancer, particularly its clinical relevance in gastric cancer (GC) remains largely unknown.MethodsRictor expression and its association with clinicopathologic characteristics in GC were analyzed by immunohistochemistry. Effect of Rictor and Caveolin-1 (Cav 1) on GC cells apoptosis was evaluated via overexpression experiment in vitro. Mechanisms of Rictor and Cav 1 in GC were explored through overexpression and knockdown, by immunofluorescence and western blot analyses.ResultsRictor was upregulated in GC, and mainly located in the cytoplasm of cancer cells. Moreover, higher Rictor levels were associated with worse prognosis. Rictor could inhibit GC cell apoptosis and promote cell growth in vitro. The results of immunofluorescence revealed that Cav 1 localized in GC cell membrane but did not co-localize with Rictor. Further, Rictor regulated apoptosis-related proteins, long non-coding RNAs and also activated cellular signaling, thereby positively regulating Cav 1 expression. This effect was attenuated by the Akt inhibitor ly294002. Cav 1 did not significantly affect the ability of Rictor to inhibit tumor cell apoptosis.ConclusionsRictor is upregulated in GC and associated with worse prognosis. It inhibits tumor apoptosis and activates Cav 1 through the Akt signaling pathway to inhibit the apoptosis of GC cells. Rictor is, therefore, a promising prognostic biomarker and possible therapeutic target in GC patients.

Tumorigenic role of tacrolimus through mTORC1/C2 activation in post-transplant renal cell carcinomas

“…Our study revealed a significantly higher occurrence of tumours with mTORC2 hyperactivation among post-tx tumours compared to non-tx RCCs, indicating the role of mTORC2 activation in the development of post-tx tumours. Increased mTORC2 activity has been associated with worse prognosis in various types of tumours, such as endometrial cancer [ 55 ], gastric cancer [ 56 ], colon cancer [ 57 ] and small cell lung cancer [ 58 ]. Higher incidence of mTORC2 hyperactivation among post-tx tumours, along with the role of mTORC2 in migration and metabolism may explain the increased cancer-specific mortality observed in recipients with cancer compared to non-tx patients [ 59 ].…”

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“…It has been found to amplify in endometrial cancer, colorectal cancer, pancreatic cancer, and malignant melanoma. Immunohistochemical results also showed that increased Rictor expression often accelerated tumor progression in gastric cancer patients and was associated with poor patient prognosis . Overexpression of Rictor in glioma cell lines led to increased mTORC2 activity, which made mTORC2 highly activated in glioma and promoted tumor cell proliferation and invasion .…”

“…Immunohistochemical results also showed that increased Rictor expression often accelerated tumor progression in gastric cancer patients and was associated with poor patient prognosis. 96 Overexpression of Rictor in glioma cell lines led to increased mTORC2 activity, which made mTORC2 highly activated in glioma and promoted tumor cell proliferation and invasion. 97 In addition, studies have shown that Raptor can interact with Rictor in tumor angiogenesis, promote colon cancer angiogenesis, and is associated with clinicopathological factors such as colorectal cancer differentiation and lymph node metastasis.…”

Roles of Rictor alterations in gastrointestinal tumors (Review)

“…Wang et al ( 33 ) found that Rictor protein overexpression and Rictor and Helicobacter pylori status may have a prognostic role in GC. A previous study by our group showed that Rictor inhibits apoptosis of GC cells by activating Cav1 through the Akt signaling pathway ( 29 ). Seo et al ( 18 ) reported that miR-let-7A regulates autophagy by targeting Rictor in GC cells.…”

“…Rictor overexpression in GC is associated with poor prognosis. In particular, Rictor activates caveolin 1 (Cav1) through the Akt signaling pathway to inhibit the apoptosis of GC cells ( 29 ). Liu et al ( 30 ) reported that real-time PCR and western blot showed that miR-153 downregulated the expression of Rictor, and this was related to the anti-tumor effect through increasing apoptosis and inhibiting the growth of breast cancer cells.…”