Inhibition of mTOR signaling reduces PELP1-mediated tumor growth and therapy resistance

Vijay K. Gonugunta, Gangadhara R Sareddy, Samaya Rajeshwari Krishnan, Valerie Cortez, Sudipa Saha Roy, Rajeshwar R Tekmal, Ratna K Vadlamudi

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 phosphoinositide 3-kinase (PI3K). However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unclear. In this study, we discovered that PELP1 cross-talked with the serine/threonine protein kinase mTOR 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 and AZD8055) significantly reduced proliferation of PELP1-overexpressed breast cancer cells in 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 PELP1cyto cells to hormonal therapy in xenograft assays. Notably, immunohistochemical 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.

Original languageEnglish (US)
Pages (from-to)1578-1588
Number of pages11
JournalMolecular Cancer Therapeutics
Volume13
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Growth
Neoplasms
Therapeutics
Heterografts
human PELP1 protein
Breast Neoplasms
Estrogen Receptors
Cytoplasm
1-Phosphatidylinositol 4-Kinase
Proto-Oncogenes
Protein-Serine-Threonine Kinases
MCF-7 Cells
Sirolimus
Drug Delivery Systems
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Inhibition of mTOR signaling reduces PELP1-mediated tumor growth and therapy resistance. / Gonugunta, Vijay K.; Sareddy, Gangadhara R; Krishnan, Samaya Rajeshwari; Cortez, Valerie; Roy, Sudipa Saha; Tekmal, Rajeshwar R; Vadlamudi, Ratna K.

In: Molecular Cancer Therapeutics, Vol. 13, No. 6, 2014, p. 1578-1588.

Research output: Contribution to journalArticle

Gonugunta, Vijay K. ; Sareddy, Gangadhara R ; Krishnan, Samaya Rajeshwari ; Cortez, Valerie ; Roy, Sudipa Saha ; Tekmal, Rajeshwar R ; Vadlamudi, Ratna K. / Inhibition of mTOR signaling reduces PELP1-mediated tumor growth and therapy resistance. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 6. pp. 1578-1588.
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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 phosphoinositide 3-kinase (PI3K). However, the mechanism by which PELP1 extranuclear actions contributes to cancer progression and therapy resistance remains unclear. In this study, we discovered that PELP1 cross-talked with the serine/threonine protein kinase mTOR 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 and AZD8055) significantly reduced proliferation of PELP1-overexpressed breast cancer cells in 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 PELP1cyto cells to hormonal therapy in xenograft assays. Notably, immunohistochemical 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.",
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