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

Abstract

Simple SummaryColorectal cancer (CRC) is the most common type of gastrointestinal cancer and the third most predominant cancer in the world. CRC is potentially curable with surgical resection of the primary tumor. The clinical problem of colorectal cancer, however, is the spread and outgrowth of metastases, which are difficult to eradicate and lead to a patient’s death. The failure of conventional treatment to significantly improved outcomes in mCRC has prompted the search for alternative molecular targets with the goal of ameliorating the prognosis of these patients. The present investigation revealed that exogenous delivery of hydrogen sulfide (H2S) suppresses proliferation in metastatic colorectal cancer cells by inducing an increase in intracellular Ca2+ concentration. H2S was effective on metastatic, but not normal, cells. Therefore, we propose that exogenous administration of H2S to patients affected by metastatic colorectal carcinoma could represent a promising therapeutic alternative.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.