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  • Original Paper
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Induction of apoptosis by the synthetic retinoid MX3350-1 through extrinsic and intrinsic pathways in head and neck squamous carcinoma cells

Abstract

Retinoids have shown promise in cancer prevention and therapy. As some retinoids exhibit undesirable side effects, new retinoid analogs have been synthesized. In this study, we examined the effects of the retinoid MX3350-1 on human head and neck squamous cell carcinoma (HNSCC) cell lines. MX3350-1 suppressed the growth of 7/8 HNSCC cell lines by >65%. This inhibition appeared to be due to induction of apoptosis as revealed by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Studies with cell line UMSCC17B indicated that apoptosis was induced within 1–2 days and involved activation of caspase-8, -9, and -3. Inhibitors of these caspases suppressed MX3350-1-induced apoptosis. MX3350-1 decreased the levels of antiapoptotic Bcl-2 and Bcl-XL, increased proapoptotic Bax, induced mitochondrial membrane permeabilization (MMP), and cytochrome c release from mitochondria to cytosol. The antioxidant butylated hydroxyanisol and the MMP inhibitor cyclosporin A (Cs A) blocked apoptosis induced by MX3350-1. In contrast, retinoid receptor antagonists failed to inhibit apoptosis. MX3350-1 increased the levels of Fas-ligand, Fas, and Fas-associated death domain, and enhanced activation of procaspase-8 and cleavage of its substrate Bid. Soluble Fas rescued the cells from MX3350-1-induced apoptosis. These results demonstrate that MX3350-1 induces apoptosis by activating both extrinsic and intrinsic apoptosis pathways and suggest that further studies on the potential of this retinoid for prevention and therapy of HNSCCs are warranted.

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Abbreviations

RA:

retinoic acid

HNSCC:

head and neck squamous cell carcinoma

RAR:

retinoic acid receptor

RXR:

retinoid X receptor

SRB:

sulforhodamine B

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

MMP:

mitochondrial membrane permeabilization

BHA:

butylated hydroxyanisol

Cs A:

cyclosporin A

DiOC6:

3′-dihexyoxacarbocyanine iodide

CCCP:

carbonyl cyanide m-chlorophenylhydrazone

FasL:

Fas ligand

FADD:

Fas-associated death domain

sFas:

soluble Fas

MKP-1:

mitogen-activated protein kinase phosphatase-1

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Acknowledgements

This study was supported in part by USPHS Head and Neck Cancer SPORE Grant P50 CA907007 and P30 CA16672-30 from the NCI.

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Correspondence to Reuben Lotan.

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Chun, KH., Pfahl, M. & Lotan, R. Induction of apoptosis by the synthetic retinoid MX3350-1 through extrinsic and intrinsic pathways in head and neck squamous carcinoma cells. Oncogene 24, 3669–3677 (2005). https://doi.org/10.1038/sj.onc.1208339

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