鎘是環境中的污染物質，也是一種人類致癌物，當細胞遭受鎘的毒害時，會造成細胞死亡或是癌化。細胞內抵抗鎘傷害的途徑主要透過兩種方式，metallothionein (MT) 和glutathione (GSH)，而文獻指出，c-Myc會活化γ-GCS的轉錄，因此促進新生合成GSH以保護細胞免受氧化壓力的傷害。此外，c-Myc會結合到人類MT2A基因的啟動子上，顯示c-Myc也可以調控MT基因的表現。並且，文獻指出，鎘會誘導c-Myc表現，因此，本研究探討在HepG2細胞中，鎘增加c-Myc表現的機制。我們發現隨著鎘處理劑量或時間增加，c-Myc mRNA和蛋白質的含量會逐漸增加。C-Myc含量的增加和起動子活性以及蛋白質穩定性無關，而是透過增加c-Myc mRNA穩定性而增加。為了探討所涉及的機制，我們分析數種訊號分子受鎘活化的情形，結果發現，PI3K、p38、ERK和JNK會受鎘活化。然而，ERK沒有參與鎘增加c-Myc含量的機制中。進一步分析，發現mTORC2是p38的下游分子，PI3K、JNK和p38/mTORC2共同活化Akt。未處理鎘的情況下，Akt Thr450就會被磷酸化，鎘處理之後會增加Akt Thr308和Ser473的磷酸化，處理PI3K、p38或JNK抑制劑都會減少Akt這三個位置的磷酸化。活化的Akt會磷酸化Foxo1並促使其由細胞核移入細胞質。大量表現Foxo1可以減少鎘誘導增加的c-Myc含量，而Foxo1 knockdown會增加c-Myc mRNA含量。因此，鎘增加細胞內c-Myc含量是透過活化PI3K、JNK和p38/mTORC2訊號分子，這些訊號分子共同活化Akt，並且Akt磷酸化Foxo1而使其由細胞核移動到細胞質，造成細胞核的Foxo1減少而降低其下游標的基因的轉錄，這些標的基因可能影響c-Myc mRNA穩定性，結果導致c-Myc mRNA穩定性增加而含量增加。
我們也探討鎘誘導c-Myc含量增加所扮演的角色。處理PI3K、JNK和p38抑制劑以及c-Myc knockdown會加強鎘所造成的細胞死亡，代表c-Myc扮演保護角色。此三種抑制劑和c-Myc knockdown也會減少鎘所誘導增加的γ-GCSh mRNA和GSH含量，但不影響MT2A mRNA含量。因此，當細胞遭受鎘壓力時，c-Myc調控細胞內GSH合成，使細胞在誘發死亡路徑前，提供細胞抵抗鎘所造成的傷害。

Cadmium (Cd) is an environmental contaminant that has been classified as a human carcinogen. Exposure of Cd leads to cell death or malignant transformation. Metallothioneins (MTs) and Glutathione (GSH) are two major branches involved in protecting cells from Cd toxicity. Previous studies showed that c-Myc transcriptionally regulates γ-glutamyl-cysteine synthetase (γ-GCS), the rate-limiting enzyme catalyzing GSH biosynthesis. In addition, c-Myc was reported to associate with MT gene expression. Cd is known to activate c-Myc proto-oncogene. However, the mechanism has not been explored. We investigated here the mechanism of c-Myc expression under Cd treatment in HepG2 cells. The c-Myc protein and mRNA levels increased with dose- and time-dependent manners after Cd treatment. This increase was not associated with promoter activity and protein stability of c-Myc but was due to an increase in c-Myc mRNA stability. To explore the mechanism involved in enhancing the mRNA stability, several cellular signaling factors that evoked by Cd treatment were analyzed. PI3K, p38, ERK and JNK were activated after Cd treatment. However, ERK did not participate in the Cd-induced c-Myc expression. Further analysis revealed that mTORC2 was a downstream factor of p38. PI3K, JNK and p38/mTORC2 coordinately activated Akt. Akt was phosphorylated at Thr450 in the untreated cells. Cd treatment led to additional phosphorylation at Thr308 and Ser473. Blocking any of the three signaling factors resulted in the reduction of phosphorylation level at all three Akt sites. The activated Akt phosphorylated Foxo1 and allowed the modified protein to translocate into the cytoplasm. Overexpression of Foxo1 reduced the Cd-induced c-Myc mRNA and protein levels, and knockdown of Foxo1 increased c-Myc mRNA level. These results suggest that Cd-induced accumulation of c-Myc requires the activation of PI3K、JNK and p38/mTORC2 signaling pathways. The signals act coordinately for Akt activation and drive the Foxo1 from the nucleus to the cytoplasm. Reduction of Foxo1 in the nucleus reduces the transcription of its target genes that may affect c-Myc mRNA stability, resulting in a higher accumulation of the c-Myc proteins. PI3K、JNK、p38 inhibitors and c-Myc knockdown enhanced Cd-induced cell death. These inhibitors and c-Myc knockdown also reduced Cd-induced γ-GCS mRNA level and GSH content, but did not affect MT2A mRNA level. These results suggest that Cd-induced c-Myc level may regulate GSH synthesis and provide protection from Cd-induced toxicity.

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