What question did this study set out to answer?

This study aims to elucidate the role of Pdcd4 in suppressing lung cancer growth through its interaction with Rictor and mTORC2.

July 4, 2026

Abstract P45: Disruption of mTORC2 Activity by Pdcd4–Rictor Binding Attenuates Tumor Growth in NSCLC

Key Points

This study aims to elucidate the role of Pdcd4 in suppressing lung cancer growth through its interaction with Rictor and mTORC2.
Analyzed pdcd4 and rictor interactions through co-immunoprecipitation and kinase assays.
Used xenograft models in nude mice to test tumor growth suppression by wild-type and mutant pdcd4.
Conducted reverse phase protein array analysis to measure levels of PFKFB3 in pdcd4 knockdown cells.
Wild-type Pdcd4 significantly inhibited tumor cell proliferation and colony formation in vitro.
In vivo, only wild-type Pdcd4 suppressed tumor growth in nude mice.
Pdcd4 downregulated PFKFB3 through ubiquitin-proteasome-mediated degradation, with this effect reliant on Rictor binding.

Abstract

Abstract Programmed cell death 4 (Pdcd4) is a tumor suppressor frequently downregulated in various cancers, including breast, colon, liver, lung, pancreas, prostate, and skin. It inhibits tumor initiation, proliferation, invasion, and metastasis. Biochemically, Pdcd4 suppresses protein translation by inhibiting the helicase activity of eIF4A, a translation initiation factor. This inhibition is thought to reduce the expression of genes critical for tumor progression. Beyond its role in translation, we recently uncovered a translation-independent tumor-suppressive mechanism of Pdcd4. Specifically, Pdcd4 interacts with the rapamycin-insensitive companion of mTOR (Rictor), a key component of the mTORC2 complex. Domain mapping through deletion and mutation analyses identified the Rictor-binding region on Pdcd4. Co-immunoprecipitation and in vitro kinase assays showed that Pdcd4 binding to Rictor disrupts mTORC2 complex formation and inhibits its kinase activity. Reverse phase protein array analysis revealed the elevated levels of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) in Pdcd4 knockdown cells. This effect was reversed by re-expression of wild-type Pdcd4 but not by a Rictor-binding deficient mutant in Pdcd4-knockdown cells, indicating that Pdcd4 downregulates PFKFB3 protein through its interaction with Rictor. Further analysis demonstrated that Pdcd4 promotes ubiquitin-proteasome-mediated degradation of PFKFB3. Functionally, wild-type Pdcd4, but not the Rictor-binding deficient mutant, significantly suppressed tumor cell proliferation and colony formation in vitro. In vivo, only wild-type Pdcd4 inhibited tumor growth in a xenograft model using nude mice. Taken together, our findings suggest that Pdcd4 suppresses NSCLC cell growth through a novel, translation-independent mechanism involving disruption of mTORC2 complex formation via binding to Rictor, leading to reduced PFKFB3 protein abundance. Citation Format: Qing Wang, Hsin-Sheng Yang. Disruption of mTORC2 Activity by Pdcd4–Rictor Binding Attenuates Tumor Growth in NSCLC abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P45.

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