Hydrogen Sulfide-Evoked Intracellular Ca²⁺ Signals in Primary Cultures of Metastatic Colorectal Cancer Cells

• Main Authors: Pawan Faris, Federica Ferulli, Mauro Vismara, Matteo Tanzi, Sharon Negri, Agnese Rumolo, Kostantinos Lefkimmiatis, Marcello Maestri, Mudhir Shekha, Paolo Pedrazzoli, Gianni Francesco Guidetti, Daniela Montagna, Francesco Moccia
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: Cancers
• Subjects: H2S; TRPV1; NCX; cancer; metastatic colorectal carcinoma; proliferation
• Online Access: https://www.mdpi.com/2072-6694/12/11/3338
• ISSN: 2072-6694

Exogenous administration of hydrogen sulfide (H₂S) is emerging as an alternative anticancer treatment. H₂S-releasing compounds have been shown to exert a strong anticancer effect by suppressing proliferation and/or inducing apoptosis in several cancer cell types, including colorectal carcinoma (CRC). The mechanism whereby exogenous H₂S affects CRC cell proliferation is yet to be clearly elucidated, but it could involve an increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i). Herein, we sought to assess for the first time whether (and how) sodium hydrosulfide (NaHS), one of the most widely employed H₂S donors, induced intracellular Ca²⁺ signals in primary cultures of human metastatic CRC (mCRC) cells. We provided the evidence that NaHS induced extracellular Ca²⁺ entry in mCRC cells by activating the Ca²⁺-permeable channel Transient Receptor Potential Vanilloid 1 (TRPV1) followed by the Na⁺-dependent recruitment of the reverse-mode of the Na⁺/Ca²⁺ (NCX) exchanger. In agreement with these observations, TRPV1 protein was expressed and capsaicin, a selective TRPV1 agonist, induced Ca²⁺ influx by engaging both TRPV1 and NCX in mCRC cells. Finally, NaHS reduced mCRC cell proliferation, but did not promote apoptosis or aberrant mitochondrial depolarization. These data support the notion that exogenous administration of H₂S may prevent mCRC cell proliferation through an increase in [Ca²⁺]_i, which is triggered by TRPV1.