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Updated: Feb 3, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

KLF14 potentiates oxidative adaptation via modulating HO-1 signaling in castrate-resistant prostate cancer

Xiao-Hui Luo¹, Jian-Zhou Liu¹, Bo Wang¹

¹Department of Urology, Baoji Center Hospital, Baoji, Shaanxi Province, People's Republic of China.

Endocrine-Related Cancer

|November 8, 2018

Abstract:

Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration-resistant prostate cancer (CRPC). Herein, we report that, the expression of Krüppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment.

Insights

Krüppel-like factor 14 (KLF14) drives castration-resistant prostate cancer (CRPC) growth by boosting antioxidant responses. Inhibiting heme oxygenase-1 (HO-1) blocks this effect, offering a potential therapeutic strategy for CRPC.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Understanding castration-resistant prostate cancer (CRPC) mechanisms is crucial for effective treatment development.
Androgen deprivation therapy often leads to treatment resistance in prostate cancer.
Identifying key factors that promote cell growth under androgen-depleted conditions is a primary goal.

Purpose of the Study:

To investigate the role of Krüppel-like factor 14 (KLF14) in promoting cell growth in castration-resistant prostate cancer (CRPC).
To elucidate the molecular mechanisms by which KLF14 contributes to androgen-independent growth.
To explore potential therapeutic targets within the KLF14-mediated pathway for CRPC treatment.

Main Methods:

Analysis of KLF14 expression in CRPC cell lines and a mouse xenograft model.
Investigating KLF14 regulation by upstream signaling pathways (PI3K/AKT, MAPK, AMPK, PKC) and oxidative stress.
Utilizing ectopic overexpression and genetic inactivation of KLF14 and HMOX1.
Assessing the impact of heme oxygenase-1 (HO-1) inhibition using ZnPPIX in vivo.

Main Results:

KLF14 expression is significantly induced in castration-insensitive prostate cancer cells and CRPC xenograft tumors.
KLF14 promotes PCa cell growth under androgen-depleted conditions by upregulating the antioxidant response.
KLF14 enhances HMOX1 transcription via interaction with p300/CBP, leading to increased HO-1 enzyme activity.
Knockdown of HMOX1 or pharmacological inhibition of HO-1 with ZnPPIX attenuates KLF14-driven CRPC progression in vivo.

Conclusions:

KLF14 plays a critical role in driving cell proliferation and adaptation to stress in CRPC.
The KLF14-HO-1 axis represents a key adaptive mechanism promoting castration resistance.
Targeting the KLF14/HO-1 pathway holds promise as a therapeutic strategy for CRPC.

Read full analysis

Keywords:

CRPC Krüppel-like factor 14 (KLF14)heme oxygenase-1 (HO-1)oxidative stress transcriptional regulation

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