Pharmacological Targeting SHP-1-STAT3 Signaling Is a Promising Therapeutic Approach for the Treatment of Colorectal Cancer

Abstract

STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3Tyr705 level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43–induced apoptosis and decreased p-STAT3Tyr705 level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3Tyr705 level. These data suggest that SC-43–induced apoptosis mediated through the loss of p-STAT3Tyr705 was dependent on SHP-1 function. Importantly, SC-43–enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3Tyr705 signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3Tyr705expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3Tyr705 expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3Tyr705 expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC.

Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

“…In the effort to figure out how progranulin affects STAT3 Tyr705 phosphorylation, we here show that intracellular progranulin restrains the ability of pivotal STAT3 tyrosine phosphatases (i.e., SHP‐1 and SHP‐2) to interact with the transcription factor, thus sustaining STAT3 hyper‐activation. Of note, accumulating evidence indicates a tumor‐suppressive role for SHP‐1 and SHP‐2 and supports the use pharmacological strategies aimed at enhancing the activity of such tyrosine phosphatases in cancer cells (Fan et al ., ; Huang et al ., ; Qi et al ., ). Thus, targeting progranulin might represent a different approach to achieve this goal.…”

WMJ‐8‐B, a novel hydroxamate derivative, induces MDA‐MB‐231 breast cancer cell death via the SHP‐1‐STAT3‐survivin cascade

“…In contrast, protein tyrosine phosphatases (PTPs) such as Src homology 2 (SH2)‐domain containing the tyrosine phosphatase‐1 (SHP‐1) (Jung et al, ), SHP‐2 (Kim et al, ) or PTP 1B (PTP‐1B) (Gu et al, ) could dephosphorylate and thereby inactivate STAT3 signalling. There is increasing evidence that SHP‐1 activation suppresses cell proliferation and induces apoptosis in different types of malignant cells (Liu et al, ; Fan et al, ). Pharmacologically targeting SHP‐1‐STAT3 signalling may be a potential therapeutic strategy for cancer treatment.…”

Synthesis of new dithiolethione and methanethiosulfonate systems endowed with pharmaceutical interest

“…In addition, their cytotoxic activity (MTT assay) 25,26 was tested on HCT116, a human colon carcinoma cell line which expresses high levels of STAT3. 27 Among the assayed compounds, 6 was the most active (IC 50 = 84.5±9.8 µM). Since STAT3 inhibition was tested in a cell-free assay, the low correspondence between STAT3 inhibition and cytotoxicity could be related to the physicochemical properties of the compounds, which will require optimization.…”

“…mp 157.1-158. 6 (27) and 5-(methylsulfonylthio)pentanoic acid (10). The crude mixture residue was purified by column chromatography (silica gel; EtOAc/cyclohexane; in gradient); the product was eluted with 40% of EtOAc.…”

“…Yield: 91.5%. (27). To a solution of 26 (0.062 mmol) in EtOAc (4 mL), tin(II) chloride (0.310 mmol) was added and the mixture was refluxed for 4 h. The reaction was then quenched by addition of a saturated aqueous solution of NaHCO 3 until pH = 7-8 to allow the precipitation of tin salts.…”