Inhibition of mTOR Signaling Reduces PELP1-Mediated Tumor Growth and Therapy Resistance

Abstract

Proline, Glutamic acid- and Leucine-rich Protein 1 (PELP1) is a proto-oncogene that modulates estrogen receptor (ER) signaling. PELP1 expression is upregulated in breast cancer, contributes to therapy resistance, and is a prognostic marker of poor survival. In a subset of breast tumors, PELP1 is predominantly localized in the cytoplasm and PELP1 participates in extranuclear signaling by facilitating ER interactions with Src and PI3 kinases. However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unclear. In this study, we discovered that PELP1 crosstalked with the serine/threonine protein kinase mammalian target of rapamycin (mTOR) axis and modulated mTOR signaling. PELP1 knockdown significantly reduced the activation of mTOR downstream signaling components. Conversely, PELP1 overexpression excessively activated mTOR signaling components. We detected the presence of the mTOR signaling complex proteins in PELP1 immunoprecipitates. mTOR targeting drugs (Rapamycin or AZD8055) significantly reduced proliferation of PELP1 over expressed breast cancer cells both in vitro and in vivo xenograft tumor models. MCF7 cells that uniquely retain PELP1 in the cytoplasm showed resistance to hormonal therapy and mTOR inhibitors sensitized PELP1-cyto cells to hormonal therapy in xenograft assays. Notably, IHC studies using xenograft tumors derived from PELP1 overexpression model cells showed increased mTOR signaling and inhibition of mTOR rendered PELP1 driven tumors to be highly sensitive to therapeutic inhibition. Collectively, our data identified the PELP1-mTOR axis as a novel component of PELP1 oncogenic functions and suggest that mTOR inhibitor(s) will be effective chemotherapeutic agents for downregulating PELP1 oncogenic functions.

The social network of PELP1 and its implications in breast and prostate cancers

“…Patients whose tumors have high levels of cytoplasmic PELP1 respond poorly to tamoxifen therapy compared with patients whose tumors have low levels of cytoplasmic PELP1 (Kumar et al 2009). These observations are in agreement with results from an experiment in which tamoxifen-susceptible MCF-7 cells engineered to express PELP1 in cytosol (by modification the nuclear localization sequence) were found to exhibit resistance to tamoxifen , Kumar et al 2009, Gonugunta VK, Sareddy GR, Krishnan SR, Cortez V, Roy SS, Tekmal RR & Vadlamudi RK, 2014. The subcellular localization of PELP1 could be used as a biomarker of hormone sensitivity or vulnerability.…”

Oridonin inhibits mTOR signaling and the growth of lung cancer tumors

“…The activity of mTOR is essential to maintain cell growth and proliferation in the PI3K/AKTdependent pathway, as evidenced by the fact that inhibition of mTOR prevents cell proliferation and enhances the development of embryonic stem cells [27][28][29]. mTOR, a member of the phosphatidylinositol 3 kinase (PI3K) family, is a ubiquitously expressed serine/threonine kinase involved in cell growth, cellular nutrient, and protein stability.…”

PELP1: Structure, biological function and clinical significance

“…PELP1 also interacts with several kinases including c-Src (Chakravarty et al 2010a), phosphoinositide 3-kinase (PI3K) (Dimple et al 2008), epidermal growth factor receptor (EGFR) (Vadlamudi et al 2005c), integrin-linked kinase (ILK1) (Chakravarty et al 2010a), mechanistic target of rapamycin (mTOR) (Gonugunta et al 2014b) and GSK3β (Sareddy GR et al 2015). PELP1 interactions with cell cycle and growth factor signaling components suggest its potential role as a mediator of hormonal singling cross talk with cell cycle machinery.…”

“…PELP1 modulates the ESR1–Src–ILK1 signaling to promote cytoskeletal rearrangements, motility and metastasis (Chakravarty et al 2010b). PELP1 also interacts with mTOR and activates its downstream signaling (Gonugunta et al 2014b). …”

“…Results from these studies supported that inhibition of CDK2 activity has the potential to abrogate the growth of PELP1-driven, hormonal therapy–resistant cells (Nair et al 2011). The mTOR-targeting drugs rapamycin and AZD8055 significantly reduced proliferation of PELP1-overexpressed breast cancer cells in both in vitro and in vivo xenograft tumor models, suggesting that mTOR inhibitor(s) may be effective chemotherapeutic agents for downregulating PELP1 oncogenic functions (Gonugunta et al 2014b), A recent study showed that liganded PR-B enhances the proliferative responses to estradiol and IGF1 via scaffolding of ESR1-PELP1-IGF1R-containing complexes. Therefore, PR antagonists may have therapeutic utility in treating a subset of PELP1-deregulated luminal ESR1, PR positive breast cancer (Daniel et al 2015).…”