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Is Ras a potential target in treatment against cutaneous squamous cell carcinoma?
1Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, 210042, China.
Abstract:
Hyperactive retrovirus-associated DNA sequence (Ras) genes have been found in human cancers and are involved in cancer pathogenesis. Salirasib, one anti-Ras compound, was reported to exhibit antitumoral effects, but its role remains unclear in cutaneous squamous cell carcinoma (cSCC). In our study, salirasib treatment led to deregulation of c-Raf, ERK and Akt signaling, blockage of MTOR signaling, interruption on Beclin 1-related autophagy regulation, activation of apoptosis and down-regulation of some cell cycle regulatory proteins in primary human epidermal keratinocyte (HEK)s, but did not exhibit similar effects in the human cSCC cell line COLO-16. MEK inhibitor U0126 can lead to dephosphorylation of MTOR and Rictor in COLO-16 cells; however, c-Raf was not yet down-regulated after salirasib treatment in the presence of U0126. Furthermore, we verified that the Ras activity could be suppressed by salirasib, and there was no loss-of-function mutation in c-Raf in HEKs and COLO-16 cells. In summary, salirasib does not exhibit antitumoral effects in the cSCC cells in assays in vitro. We speculated that the disability of signaling transmission from Ras to c-Raf in COLO-16 cells might contribute to the ineffective performance of salirasib.
Insights
Salirasib, an anti-Ras drug, did not show anti-tumor effects on cutaneous squamous cell carcinoma (cSCC) cells in vitro. This ineffectiveness may stem from a signaling defect between Ras and c-Raf in these cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Hyperactive retrovirus-associated DNA sequence (Ras) genes are implicated in human cancer pathogenesis.
- Salirasib is an anti-Ras compound investigated for antitumoral effects, but its role in cutaneous squamous cell carcinoma (cSCC) is not well-defined.
Purpose of the Study:
- To investigate the antitumoral effects of salirasib in cutaneous squamous cell carcinoma (cSCC).
- To elucidate the molecular mechanisms underlying salirasib's efficacy or inefficacy in cSCC cells.
Main Methods:
- Treatment of primary human epidermal keratinocytes (HEKs) and a cSCC cell line (COLO-16) with salirasib.
- Analysis of signaling pathways including c-Raf, ERK, Akt, MTOR, and autophagy regulation.
- Assessment of apoptosis, cell cycle regulatory proteins, and Ras activity.
- Use of MEK inhibitor U0126 to probe signaling pathways.
Main Results:
- Salirasib induced apoptosis, blocked MTOR signaling, and affected autophagy and cell cycle proteins in HEKs, but not in COLO-16 cSCC cells.
- MEK inhibition in COLO-16 cells did not lead to c-Raf down-regulation with salirasib treatment.
- Salirasib suppressed Ras activity, and no loss-of-function mutation in c-Raf was found in either cell type.
Conclusions:
- Salirasib demonstrated no significant antitumoral effects on cSCC cells in vitro.
- A potential defect in Ras-to-c-Raf signaling transmission in COLO-16 cells may explain salirasib's ineffectiveness.
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