PiR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair

Basudeb Das,Neha Jain,Bibekanand Mallick

doi:10.1038/s42003-021-02844-1

Basudeb Das, Neha Jain + Show 1 more

Open Access

https://doi.org/10.1038/s42003-021-02844-1

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Abstract

Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. PIWI-interacting RNAs (piRNAs) have been shown to enhance patient outcomes in cancers. However, there are few or no reports on piRNAs affecting chemotherapy in cancers, including fibrosarcoma. The current study aims to investigate the relationship between piR-39980 and DOX resistance and the underlying mechanisms. We reveal that piR-39980 is less expressed in DOX-resistant HT1080 (HT1080/DOX) fibrosarcoma cells. Our results show that inhibition of piR-39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. The dual-luciferase reporter assay indicates that piR-39980 negatively regulates RRM2 and CYP1A2 via direct binding to their 3′UTRs. Furthermore, overexpressing RRM2 induces DOX resistance of HT1080 cells by rescuing DOX-induced DNA damage by promoting DNA repair, whereas CYP1A2 confers resistance by decreasing intracellular DOX accumulation, which piR-39980 restores. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX.

Highlights

Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown
We have reported that piR39980 was downregulated in HT1080 fibrosarcoma cells compared to IMR90 normal fibroblast cells and acted as a tumor suppressor by inhibiting proliferation, metastasis, and inducing apoptosis[29]
The degree of DOX resistance is calculated in terms of resistance index (R), which showed the HT1080/DOX cells were approximately five-fold more resistant to the drug than the parental HT1080 cell line

Summary

Introduction

Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. Our results show that inhibition of piR39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX. The primary treatment of fibrosarcoma consists of amputation, surgical resection of tumor tissues, and radiotherapy[2]. These strategies are not beneficial for metastatic or unresectable sarcomas. It is necessary to find new small molecules that enhance fibrosarcoma cells’ sensitivity to DOX and improve therapy clinically

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