ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma

Suma Yarapureddy, Jazmine Abril, Janet A Foote, Saravana Kumar, Omar Asad, Veena Sharath, Janine Faraj, Dustin Daniel, Paul Dickman, Andrea White-Collins, Pooja Hingorani, Aparna R Sertil

Research output: Contribution to journalArticle

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Abstract

Patients with metastatic or relapsed/refractory osteosarcoma (OS) have a 5-year survival rate of <30%. This has remained unchanged over several decades. One of the factors contributing to lack of improvement in survival is the development of chemoresistance. Hence, elucidating and targeting the mechanisms that promote survival against chemotherapy and lead to chemoresistance is pivotal to improving outcomes for these patients. We identified that endoplasmic reticulum (ER) stress-activated transcription factor, ATF6α, is essential for the survival of OS cells against chemotherapy induced cell death. ATF6α cleavage and activity were enhanced in OS cells compared to normal osteoblasts and knockdown of ATF6α expression enhanced sensitivity of OS cells against chemotherapy induced cell death. This was in part due to increased Bax activation. Pharmacologic inhibition or knock-down of downstream targets of ATF6α, protein disulfide isomerases (PDI) and ERO1β, a thiol oxidase that is involved in the re-oxidation of PDIs also independently induced pronounced killing of OS cells following chemotherapy. Analysis of primary tumors from OS patients reveals that patients with high levels of nuclear ATF6α: (1) also had increased expression of its downstream targets the chaperone BiP and enzyme PDI, (2) had a significant likelihood of developing metastasis at diagnosis, (3) had significantly poorer overall and progression free survival, and (4) had poorer response to chemotherapy. These findings suggest that targeting survival signaling by the ATF6α pathway in OS cells may favor eradication of refractory OS tumor cells and ATF6α could be a useful predictor for chemo-responsiveness and prognosis.

Original languageEnglish (US)
Pages (from-to)516-532
Number of pages17
JournalNeoplasia (New York, N.Y.)
Volume21
Issue number6
DOIs
StatePublished - Jun 1 2019

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Osteosarcoma
Drug Therapy
Survival
Protein Disulfide-Isomerases
Activating Transcription Factor 6
Cell Death
Endoplasmic Reticulum Stress
Osteoblasts
Sulfhydryl Compounds
Disease-Free Survival
Cell Survival
Oxidoreductases
Survival Rate
Neoplasm Metastasis
Enzymes

ASJC Scopus subject areas

  • Cancer Research

Cite this

ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma. / Yarapureddy, Suma; Abril, Jazmine; Foote, Janet A; Kumar, Saravana; Asad, Omar; Sharath, Veena; Faraj, Janine; Daniel, Dustin; Dickman, Paul; White-Collins, Andrea; Hingorani, Pooja; Sertil, Aparna R.

In: Neoplasia (New York, N.Y.), Vol. 21, No. 6, 01.06.2019, p. 516-532.

Research output: Contribution to journalArticle

Yarapureddy, S, Abril, J, Foote, JA, Kumar, S, Asad, O, Sharath, V, Faraj, J, Daniel, D, Dickman, P, White-Collins, A, Hingorani, P & Sertil, AR 2019, 'ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma', Neoplasia (New York, N.Y.), vol. 21, no. 6, pp. 516-532. https://doi.org/10.1016/j.neo.2019.02.004
Yarapureddy, Suma ; Abril, Jazmine ; Foote, Janet A ; Kumar, Saravana ; Asad, Omar ; Sharath, Veena ; Faraj, Janine ; Daniel, Dustin ; Dickman, Paul ; White-Collins, Andrea ; Hingorani, Pooja ; Sertil, Aparna R. / ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma. In: Neoplasia (New York, N.Y.). 2019 ; Vol. 21, No. 6. pp. 516-532.
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AU - Sharath, Veena

AU - Faraj, Janine

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