Targeting PNPO to suppress tumor growth via inhibiting autophagic flux and to reverse paclitaxel resistance in ovarian cancer

Sep 21, 2026

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Previous work identified pyridoxine 5’-phosphate oxidase (PNPO) as a tissue biomarker for ovarian cancer (OC) with prognostic value, while mechanisms and chemoresistance roles remained unclear. This study examined PNPO-regulated lysosome/autophagy pathways and found PNPO overexpression in OC cells promoted proliferation by regulating cyclin B1 and phosphorylated CDK1 and accelerated G2M. PNPO enhanced lysosome biogenesis and autophagic flux via an LAMP2-dependent axis, with LAMP2 silencing suppressing growth and inducing apoptosis. PNPO knockdown reduced xenograft tumor formation and restored paclitaxel sensitivity in vitro and in vivo, while chloroquine disrupted PNPO’s autophagy effects and inhibited survival, supporting PNPO targeting as a strategy to suppress tumor growth and reverse paclitaxel resistance.

LanguageEnglish

CategoryHealthcare

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Pages18

Reading Time45 min

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Abstract

Introduction

Ovarian cancer burden and chemoresistance

Rationale for PNPO, autophagy, and lysosomal mechanisms

Chloroquine and therapeutic context

Targeting PNPO to suppress tumor growth via inhibiting autophagic flux and to reverse paclitaxel resistance in ovarian cancer Xin Li1,2 · Wencai Guan1 · Huiqiang Liu1,2 · Jia Yuan1,2 · Fanchen Wang1,2 · Bin Guan1,2 · Junyu Chen1,2 · Qi Lu1,2,3 · Lingyun Zhang4,5 · Guoxiong Xu1,2,6 Accepted: 10 March 2024 / Published online: 13 April 2024 © The Author(s) 2024, corrected publication 2024 Abstract Our previous study showed that pyridoxine 5’-phosphate oxidase (PNPO) is a tissue biomarker of ovarian cancer (OC) and has a prognostic implication but detailed mechanisms remain unclear. The current study focused on PNPO-regulated lysosome/autophagy-mediated cellular processes and the potential role of PNPO in chemoresistance. We found that PNPO was overexpressed in OC cells and was a prognostic factor in OC patients. PNPO significantly promoted cell proliferation via the regulation of cyclin B1 and phosphorylated CDK1 and shortened the G2M phase in a cell cycle. Overexpressed PNPO enhanced the biogenesis and perinuclear distribution of lysosomes, promoting the degradation of autophagosomes and boosting the autophagic flux. Further, an autolysosome marker LAMP2 was upregulated in OC cells. Silencing LAMP2 suppressed cell growth and induced cell apoptosis. LAMP2-siRNA blocked PNPO action in OC cells, indicating that the function of PNPO on cellular processes was mediated by LAMP2 . These data suggest the existence of the PNPO-LAMP2 axis. Moreover, silencing PNPO suppressed xenographic tumor formation. Chloroquine counteracted the promotion effect of PNPO on autophagic flux and inhibited OC cell survival, facilitating the inhibitory effect of PNPO-shRNA on tumor growth in vivo. Finally, PNPO was overexpressed in paclitaxel-resistant OC cells. PNPO-siRNA enhanced paclitaxel sensitivity in vitro and in vivo. In conclusion, PNPO has a regulatory effect on lysosomal biogenesis that in turn promotes autophagic flux, leading to OC cell proliferation, and tumor formation, and is a paclitaxel-resistant factor. These data imply a potential application by targeting PNPO to suppress tumor growth and reverse PTX resistance in OC. Keywords Autophagy · Chemoresistance · Lysosome · Pyridox(am)ine-5'-phosphate oxidase · Reversal · Tumorigenesis 􀀍 Lingyun Zhang [lingyunzhang15@fudan.edu.cn](lingyunzhang15@fudan.edu.cn) 􀀍 Guoxiong Xu [guoxiong.xu@fudan.edu.cn](guoxiong.xu@fudan.edu.cn) 1 Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, 1508 Longhang Road, Shanghai 201508, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 3 Department of Obstetrics and Gynecology, Jinshan Hospital, Fudan University, Shanghai, China 4 Department of Medical Oncology, Shanghai Geriatric Medical Center, Shanghai, China 5 Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China 6 Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China Introduction Ovarian cancer (OC) is the second most lethal gynecological malignancy worldwide [1] . In 2023, the estimated number of new cases and deaths of OC is 19,710 and 13,270, respectively, in the United States [2] . Epithelial ovarian cancer (EOC) represents over 90% of ovarian malignancies [3] . Because of the asymptomatic at the early stage, the majority of EOC patients are diagnosed at the advanced stage, leading to an unfavorable prognosis due to recurrence and chemoresistance [4] . The standard treatment for EOCis cytoreductive surgery combined with paclitaxel (PTX) and carboplatin. However, about 70% of patients with stage III-IV faced chemoresistance and relapsed within 3 years [3, 5] . Therefore, the development of reliable early detection methods and overcoming chemoresistance is crucial for improving the prognosis of patients with OC. Pyridox(am)ine-5’-phosphate oxidase (PNPO) is an enzymic protein for the synthesis of pyridoxal 5’-phosphate (PLP), an active form of vi

FAQs

How does PNPO influence ovarian cancer cell proliferation and the cell cycle?

PNPO promotes OC cell proliferation by regulating cyclin B1 and phosphorylated CDK1, which shortens the G2M phase of the cell cycle.

What role does LAMP2 play in PNPO-mediated autophagy?

Overexpressed PNPO increases lysosome biogenesis and distribution, leading to enhanced autophagic flux. LAMP2 upregulation and LAMP2 silencing suppress growth and induce apoptosis, and LAMP2-siRNA blocks PNPO’s effects.

Can targeting PNPO affect paclitaxel resistance and tumor growth in vivo?

PNPO is overexpressed in paclitaxel-resistant OC cells, and PNPO-siRNA enhances paclitaxel sensitivity in vitro and in vivo. Silencing PNPO also suppresses xenograft tumor formation, while chloroquine counteracts PNPO’s autophagy-linked survival effects.

Sep 21, 2026

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