Elevating SOX2 in prostate tumor cells upregulates expression of neuroendocrine genes, but does not reduce the inhibitory effects of enzalutamide

Ethan P. Metz, Phillip J. Wilder, Jixin Dong, Kaustubh Datta, Angie Rizzino

Research output: Contribution to journalArticle

Abstract

Prostate cancer (PCa) is one of the leading causes of cancer deaths in men. In this cancer, the stem cell transcription factor SOX2 increases during tumor progression, especially as the cancer progresses to the highly aggressive neuroendocrine-like phenotype. Other studies have shown that knockdown of RB1 and TP53 increases the expression of neuroendocrine markers, decreases the sensitivity to enzalutamide, and increases the expression of SOX2. Importantly, knockdown of SOX2 in the context of RB1 and TP53 depletion restored sensitivity to enzalutamide and reduced the expression of neuroendocrine markers. In this study, we examined whether elevating SOX2 is not only necessary, but also sufficient on its own to promote the expression of neuroendocrine markers and confer enzalutamide resistance. For this purpose, we engineered LNCaP cells for inducible overexpression of SOX2 (i-SOX2–LNCaP). As shown previously for other tumor cell types, inducible elevation of SOX2 in i-SOX2–LNCaP inhibited cell proliferation. SOX2 elevation also increased the expression of several neuroendocrine markers, including several neuropeptides and synaptophysin. However, SOX2 elevation did not decrease the sensitivity of i-SOX2–LNCaP cells to enzalutamide, which indicates that elevating SOX2 on its own is not sufficient to confer enzalutamide resistance. Furthermore, knocking down SOX2 in C4-2B cells, a derivative of LNCaP cells which is far less sensitive to enzalutamide and which expresses much higher levels of SOX2 than LNCaP cells, did not alter the growth response to this antiandrogen. Thus, our studies indicate that NE marker expression can increase independently of the sensitivity to enzalutamide.

Original languageEnglish (US)
Pages (from-to)3731-3740
Number of pages10
JournalJournal of Cellular Physiology
Volume235
Issue number4
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Tumors
Prostate
Up-Regulation
Genes
Cells
Gene Expression
Neoplasms
SOXB1 Transcription Factors
Androgen Antagonists
Synaptophysin
Stem Cell Factor
Cell proliferation
MDV 3100
Stem cells
Neuropeptides
Cause of Death
Prostatic Neoplasms
Transcription Factors
Cell Proliferation
Derivatives

Keywords

  • PSA
  • SOX2
  • enzalutamide
  • neuroendocrine
  • notch signaling
  • prostate tumor cells

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Elevating SOX2 in prostate tumor cells upregulates expression of neuroendocrine genes, but does not reduce the inhibitory effects of enzalutamide. / Metz, Ethan P.; Wilder, Phillip J.; Dong, Jixin; Datta, Kaustubh; Rizzino, Angie.

In: Journal of Cellular Physiology, Vol. 235, No. 4, 01.04.2020, p. 3731-3740.

Research output: Contribution to journalArticle

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abstract = "Prostate cancer (PCa) is one of the leading causes of cancer deaths in men. In this cancer, the stem cell transcription factor SOX2 increases during tumor progression, especially as the cancer progresses to the highly aggressive neuroendocrine-like phenotype. Other studies have shown that knockdown of RB1 and TP53 increases the expression of neuroendocrine markers, decreases the sensitivity to enzalutamide, and increases the expression of SOX2. Importantly, knockdown of SOX2 in the context of RB1 and TP53 depletion restored sensitivity to enzalutamide and reduced the expression of neuroendocrine markers. In this study, we examined whether elevating SOX2 is not only necessary, but also sufficient on its own to promote the expression of neuroendocrine markers and confer enzalutamide resistance. For this purpose, we engineered LNCaP cells for inducible overexpression of SOX2 (i-SOX2–LNCaP). As shown previously for other tumor cell types, inducible elevation of SOX2 in i-SOX2–LNCaP inhibited cell proliferation. SOX2 elevation also increased the expression of several neuroendocrine markers, including several neuropeptides and synaptophysin. However, SOX2 elevation did not decrease the sensitivity of i-SOX2–LNCaP cells to enzalutamide, which indicates that elevating SOX2 on its own is not sufficient to confer enzalutamide resistance. Furthermore, knocking down SOX2 in C4-2B cells, a derivative of LNCaP cells which is far less sensitive to enzalutamide and which expresses much higher levels of SOX2 than LNCaP cells, did not alter the growth response to this antiandrogen. Thus, our studies indicate that NE marker expression can increase independently of the sensitivity to enzalutamide.",
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