Hydrogen sulfide in cancer: Friend or foe?

Highlights

• Hydrogen sulfide (H₂S) has opposite effects on cancer: pro-cancer and anti-cancer.

• Endogenous H₂S promotes cancer development and progression.

• Inhibition of endogenous H₂S production may be a new strategy for cancer treatment.

• Relatively high concentration of exogenous H₂S suppresses growth of cancer cells.

• H₂S donors and H₂S-releasing hybrids could be developed as novel anti-cancer drugs.

Abstract

Hydrogen sulfide (H₂S) is the third gaseous signaling molecule that plays important roles in cancer biological processes. Recent studies indicate that H₂S has both pro-cancer and anti-cancer effects. Endogenous H₂S can exert pro-cancer functions through induction of angiogenesis regulation of mitochondrial bioenergetics, acceleration of cell cycle progression, and anti-apoptosis mechanisms. Thus, the inhibition of the production of H₂S in cancer cells may be a new cancer treatment strategy. In contrast to the pro-cancer effect of H₂S, relatively high concentrations of exogenous H₂S could suppress the growth of cancer cells by inducing uncontrolled intracellular acidification, inducing cell cycle arrest, and promoting apoptosis. Therefore, H₂S donors and H₂S-releasing hybrids could be designed and developed as novel anti-cancer drugs. In this review, the production and metabolism of H₂S in cancer cells are summarized and the role and mechanism of H₂S in cancer development and progression are further discussed.

Introduction

Hydrogen sulfide (H₂S) was known only as an environmental pollutant for several centuries but is now widely considered an important biological and pharmacological mediator. In mammals, endogenous H₂S mainly comes from the metabolism of l-cysteine and homocysteine by the catalysis of two pyridoxal-5′-phosphate (PLP)-dependent enzymes, termed cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). Both CSE and CBS are cytosolic enzymes [1], [2], [3]. 3-Mercaptopyruvate sulfurtransferase (3-MST), a PLP-independent enzyme, acts in combination with cysteine aminotransferase (CAT) to produce H₂S from l-cysteine in the presence of α-ketoglutarate [4]. CAT and 3-MST are localized in both the cytosol and mitochondria [1], [5]. Once formed, H₂S can be immediately released or stored as bound and acid-labile sulfur in the cells [6].

H₂S has been recognized as the third endogenous gasotransmitter in mammals, along with nitric oxide and carbon monoxide [7], [8], [9]. A number of studies have shown that H₂S is involved in many physiological and pathophysiological functions [1], [2], [5], [8], [9], [10], [11], [12]. Nevertheless, there has been some controversy on the role of H₂S in cancer development and progression. In multicellular organisms, normal cellular homeostasis is maintained through a balance between the processes of cell proliferation and cell death. Aberrations in cell survival could disrupt the normal cell cycle regulation and initiate tumor formation and metastasis [13], [14], [15]. In recent years, an increasing amount of evidence suggests that exogenously administered and/or endogenously produced H₂S could exhibit two obviously opposite functions on the growth of cancer cells [16], [17], [18], [19]. Therefore, it is urgent and essential to illuminate the effect and mechanism of H₂S on the growth and proliferation of cancer cells.

In this review, we highlight recent studies that provide new insight into the production and metabolism of H₂S in cancer cells, as well as further discuss the role and mechanism of H₂S in cancer development and progression.