Inhibition and potential treatment of colorectal cancer by natural compounds via various signaling pathways

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME’s cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/β-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/β-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

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Unraveling the Complex Interconnection between Specific Inflammatory Signaling Pathways and Mechanisms Involved in HIV-Associated Colorectal Oncogenesis

Damane

Mulaudzi

Kader

et al. 2023

Cancers

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The advancement of HIV treatment has led to increased life expectancy. However, people living with HIV (PLWH) are at a higher risk of developing colorectal cancers. Chronic inflammation has a key role in oncogenesis, affecting the initiation, promotion, transformation, and advancement of the disease. PLWH are prone to opportunistic infections that trigger inflammation. It has been documented that 15–20% of cancers are triggered by infections, and this percentage is expected to be increased in HIV co-infections. The incidence of parasitic infections such as helminths, with Ascariasis being the most common, is higher in HIV-infected individuals. Cancer cells and opportunistic infections drive a cascade of inflammatory responses which assist in evading immune surveillance, making them survive longer in the affected individuals. Their survival leads to a chronic inflammatory state which further increases the probability of oncogenesis. This review discusses the key inflammatory signaling pathways involved in disease pathogenesis in HIV-positive patients with colorectal cancers. The possibility of the involvement of co-infections in the advancement of the disease, along with highlights on signaling mechanisms that can potentially be utilized as therapeutic strategies to prevent oncogenesis or halt cancer progression, are addressed.

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Inhibition and potential treatment of colorectal cancer by natural compounds via various signaling pathways

Cited by 5 publications

References 217 publications

Recent Advancements in the Inhibition of Metastasis of Colorectal Cancer Using Anticancer Compounds

Recent Advancements in the Inhibition of Metastasis of Colorectal Cancer Using Anticancer Compounds

Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether

Unraveling the Complex Interconnection between Specific Inflammatory Signaling Pathways and Mechanisms Involved in HIV-Associated Colorectal Oncogenesis

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