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IL-32α suppresses colorectal cancer development via TNFR1-mediated death signaling.

Yun HM, Park KR, Kim EC, Han SB, Yoon do Y, Hong JT - Oncotarget (2015)

Bottom Line: Also, IL-32α increased ROS production to induce prolonged JNK activation.In colon cancer patients, IL-32α and TNFR1 were increased.These findings indicate that IL-32α suppressed colon cancer development by promoting the death signaling of TNFR1.

View Article: PubMed Central - PubMed

Affiliation: Department of Maxillofacial Tissue Regeneration, School of Dentistry and Research Center for Tooth & Periodontal Regeneration (MRC), Kyung Hee University, Seoul 130-701, Republic of Korea.

ABSTRACT
Inflammation is associated with cancer-prone microenvironment, leading to cancer. IL-32 is expressed in chronic inflammation-linked human cancers. To investigate IL-32α in inflammation-linked colorectal carcinogenesis, we generated a strain of mice, expressing IL-32 (IL-32α-Tg). In IL-32α-Tg mice, azoxymethane (AOM)-induced colon cancer incidence was decreased, whereas expression of TNFR1 and TNFR1-medicated apoptosis was increased. Also, IL-32α increased ROS production to induce prolonged JNK activation. In colon cancer patients, IL-32α and TNFR1 were increased. These findings indicate that IL-32α suppressed colon cancer development by promoting the death signaling of TNFR1.

No MeSH data available.


Related in: MedlinePlus

Effects of IL-32α on ROS release and JNK activation in cancer tissues and colon cancer cells(A) Cells were treated with 30 ng/ml TNFα for 4 hr in SW-pcDNA cells and SW-IL-32α cells. *Significant difference from SW-pcDNA cells (**p < 0.01). (B) SW-IL-32α cells were treated with TNFα for 4 hr in the absence or presence of the NOX inhibitor, DPI (20 μM) for 30 min. ROS levels were determined using ROS detection kit as described in Materials and Methods section. *Significant difference from control or TNFα-treated cell (**p < 0.01). (C) After SW-IL-32α cells were treated with TNFα for 60 min in the absence or presence of DPI (20 μM) for 30 min, cell extracts were analyzed by Western blotting using anti-phospho-JNK and anti-JNK antibodies. (D, E) Cancer extracts were analyzed by Western blotting (D) and ROS detection kit (E) as described in Materials and Methods section. *Significant difference from non-Tg mice (**p < 0.01). Representative results shown in Figure 4 were repeated in triplicate with similar results.
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Figure 4: Effects of IL-32α on ROS release and JNK activation in cancer tissues and colon cancer cells(A) Cells were treated with 30 ng/ml TNFα for 4 hr in SW-pcDNA cells and SW-IL-32α cells. *Significant difference from SW-pcDNA cells (**p < 0.01). (B) SW-IL-32α cells were treated with TNFα for 4 hr in the absence or presence of the NOX inhibitor, DPI (20 μM) for 30 min. ROS levels were determined using ROS detection kit as described in Materials and Methods section. *Significant difference from control or TNFα-treated cell (**p < 0.01). (C) After SW-IL-32α cells were treated with TNFα for 60 min in the absence or presence of DPI (20 μM) for 30 min, cell extracts were analyzed by Western blotting using anti-phospho-JNK and anti-JNK antibodies. (D, E) Cancer extracts were analyzed by Western blotting (D) and ROS detection kit (E) as described in Materials and Methods section. *Significant difference from non-Tg mice (**p < 0.01). Representative results shown in Figure 4 were repeated in triplicate with similar results.

Mentions: Sustained JNK activation appears to correlate with ROS generation and cell death. Thus, it was further investigated whether IL-32α elevated ROS generation in colon cancer. As shown in Figure 4, SW-IL-32α cells significantly increased ROS level (Figure 4A), which was prevented by an inhibitor of nicotinamide adenine dinucleotide phosphate-oxidase (NOX), DPI (Figure 4B). The pretreatment of DPI also inhibited prolonged JNK activation (phospho-JNK) (Figure 4C). It was validated that the knockdown of TNFR1 significantly attenuated ROS generation in SW-IL-32α cells (Supplementary Figure 2). In parallel with colon cancer cell growth, the phosphorylation of JNK (Figure 4D) and the level of ROS (Figure 4E) were also increased in IL-32α Tg mice compared to non-Tg mice. These data suggest that ROS-JNK signaling of TNFR1 is critical mediator of IL-32α-mediated anti-cancer effect.


IL-32α suppresses colorectal cancer development via TNFR1-mediated death signaling.

Yun HM, Park KR, Kim EC, Han SB, Yoon do Y, Hong JT - Oncotarget (2015)

Effects of IL-32α on ROS release and JNK activation in cancer tissues and colon cancer cells(A) Cells were treated with 30 ng/ml TNFα for 4 hr in SW-pcDNA cells and SW-IL-32α cells. *Significant difference from SW-pcDNA cells (**p < 0.01). (B) SW-IL-32α cells were treated with TNFα for 4 hr in the absence or presence of the NOX inhibitor, DPI (20 μM) for 30 min. ROS levels were determined using ROS detection kit as described in Materials and Methods section. *Significant difference from control or TNFα-treated cell (**p < 0.01). (C) After SW-IL-32α cells were treated with TNFα for 60 min in the absence or presence of DPI (20 μM) for 30 min, cell extracts were analyzed by Western blotting using anti-phospho-JNK and anti-JNK antibodies. (D, E) Cancer extracts were analyzed by Western blotting (D) and ROS detection kit (E) as described in Materials and Methods section. *Significant difference from non-Tg mice (**p < 0.01). Representative results shown in Figure 4 were repeated in triplicate with similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4496202&req=5

Figure 4: Effects of IL-32α on ROS release and JNK activation in cancer tissues and colon cancer cells(A) Cells were treated with 30 ng/ml TNFα for 4 hr in SW-pcDNA cells and SW-IL-32α cells. *Significant difference from SW-pcDNA cells (**p < 0.01). (B) SW-IL-32α cells were treated with TNFα for 4 hr in the absence or presence of the NOX inhibitor, DPI (20 μM) for 30 min. ROS levels were determined using ROS detection kit as described in Materials and Methods section. *Significant difference from control or TNFα-treated cell (**p < 0.01). (C) After SW-IL-32α cells were treated with TNFα for 60 min in the absence or presence of DPI (20 μM) for 30 min, cell extracts were analyzed by Western blotting using anti-phospho-JNK and anti-JNK antibodies. (D, E) Cancer extracts were analyzed by Western blotting (D) and ROS detection kit (E) as described in Materials and Methods section. *Significant difference from non-Tg mice (**p < 0.01). Representative results shown in Figure 4 were repeated in triplicate with similar results.
Mentions: Sustained JNK activation appears to correlate with ROS generation and cell death. Thus, it was further investigated whether IL-32α elevated ROS generation in colon cancer. As shown in Figure 4, SW-IL-32α cells significantly increased ROS level (Figure 4A), which was prevented by an inhibitor of nicotinamide adenine dinucleotide phosphate-oxidase (NOX), DPI (Figure 4B). The pretreatment of DPI also inhibited prolonged JNK activation (phospho-JNK) (Figure 4C). It was validated that the knockdown of TNFR1 significantly attenuated ROS generation in SW-IL-32α cells (Supplementary Figure 2). In parallel with colon cancer cell growth, the phosphorylation of JNK (Figure 4D) and the level of ROS (Figure 4E) were also increased in IL-32α Tg mice compared to non-Tg mice. These data suggest that ROS-JNK signaling of TNFR1 is critical mediator of IL-32α-mediated anti-cancer effect.

Bottom Line: Also, IL-32α increased ROS production to induce prolonged JNK activation.In colon cancer patients, IL-32α and TNFR1 were increased.These findings indicate that IL-32α suppressed colon cancer development by promoting the death signaling of TNFR1.

View Article: PubMed Central - PubMed

Affiliation: Department of Maxillofacial Tissue Regeneration, School of Dentistry and Research Center for Tooth & Periodontal Regeneration (MRC), Kyung Hee University, Seoul 130-701, Republic of Korea.

ABSTRACT
Inflammation is associated with cancer-prone microenvironment, leading to cancer. IL-32 is expressed in chronic inflammation-linked human cancers. To investigate IL-32α in inflammation-linked colorectal carcinogenesis, we generated a strain of mice, expressing IL-32 (IL-32α-Tg). In IL-32α-Tg mice, azoxymethane (AOM)-induced colon cancer incidence was decreased, whereas expression of TNFR1 and TNFR1-medicated apoptosis was increased. Also, IL-32α increased ROS production to induce prolonged JNK activation. In colon cancer patients, IL-32α and TNFR1 were increased. These findings indicate that IL-32α suppressed colon cancer development by promoting the death signaling of TNFR1.

No MeSH data available.


Related in: MedlinePlus