miR-3132 upregulates surface TRAIL to induce apoptotic cell death in cancer cells

Amriti R Lulla; Yan Zhou; Marie D Ralff; Avital Lev; David T Dicker; Wafik S El-Deiry

miR-3132 upregulates surface TRAIL to induce apoptotic cell death in cancer cells

Am J Cancer Res. 2022 Jan 15;12(1):315-326. eCollection 2022.

Authors

Amriti R Lulla^{1

2}, Yan Zhou³, Marie D Ralff^{1

4}, Avital Lev¹, David T Dicker¹, Wafik S El-Deiry^{1

5

6

7

8}

Affiliations

¹ Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center Philadelphia, PA, USA.
² Graduate Program in Molecular Medicine, Penn State College of Medicine Hershey, PA, USA.
³ Molecular Therapeutics Program, Fox Chase Cancer Center Philadelphia, PA, USA.
⁴ MD/PhD Program, The Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA.
⁵ Joint Program in Cancer Biology, Brown University and The Lifespan Health System Providence, RI, USA.
⁶ Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University Providence, RI, USA.
⁷ Hematology-Oncology Division, Brown University and The Lifespan Cancer Institute Providence, RI, USA.
⁸ Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University Providence, RI, USA.

PMID: 35141020
PMCID: PMC8822281

Abstract

TRAIL-based therapies are of significant clinical interest because of its unique ability to induce apoptosis in cancer cells while sparing normal and untransformed cells. This selective antitumor potential of the TRAIL pathway has been harnessed by development of therapeutics including recombinant (rh)TRAIL and TRAIL-receptor agonist antibodies such as mapatumumab and lexatumumab. While these TRAIL-based therapies have proven successful in preclinical studies and safe in early phase clinical trials, the limited serum half-life has been a hurdle for further clinical development. Here we characterize miR-3132, a novel and first-in class TRAIL-inducing miRNA with potent anti-proliferative and pro-apoptotic effects in cancer cell lines. Initial mechanistic studies indicate that miR-3132 engages the interferon signaling pathway to induce TRAIL and subsequent TRAIL-dependent apoptosis in cancer cell lines. Our data further suggests that the binding of miR-3132 to toll-like receptors could be the upstream pathway for the interferon response. The current study the first report to demonstrate miR-3132's in vitro efficacy and preliminary mechanism of action in cancer cell lines.

Keywords: TRAIL; cell death; colon cancer; miR-3132; miRNA.