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Distinct apoptotic responses imparted by c-myc and max
1Section of Hematology/Oncology, the Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Abstract:
The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc- and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc-overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc-overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways.
Insights
The c-myc and max proteins, crucial for cell growth, influence programmed cell death (apoptosis) differently. Overexpression of c-myc or max in myeloid cells alters their sensitivity to chemotherapy and cytokine deprivation, revealing distinct apoptotic pathways.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- The c-myc oncoprotein is known to accelerate programmed cell death (apoptosis).
- Max, the heterodimeric partner of c-myc, also promotes apoptosis.
- Understanding the distinct roles of c-myc and max in apoptosis is crucial for cancer therapy.
Purpose of the Study:
- To investigate the differential apoptotic responses of cells overexpressing c-myc versus max.
- To determine how these proteins affect sensitivity to chemotherapeutic agents and cytokine deprivation.
- To elucidate the mechanistic underpinnings of distinct apoptotic pathways modulated by c-myc and max.
Main Methods:
- Overexpression of c-myc and max in 32D murine myeloid cells.
- Treatment with chemotherapeutic compounds (Etoposide, Adriamycin, Camptothecin, Taxol).
- Cytokine (interleukin-3) deprivation experiments.
- Analysis of apoptosis rates and cell cycle arrest (G1, G2/M).
- Ectopic expression of apoptosis inhibitors Bcl-2 and Bcl-XL.
Main Results:
- c-myc overexpression enhanced sensitivity to Etoposide, Adriamycin, and Camptothecin, while max overexpression primarily increased sensitivity to Camptothecin in the presence of IL-3.
- Max-overexpressing cells showed enhanced sensitivity to Adriamycin, Etoposide, and Taxol upon IL-3 deprivation.
- Bcl-2 blocked apoptosis in both cell types under all conditions, whereas Bcl-XL specifically blocked apoptosis in max-overexpressing cells during IL-3 withdrawal.
Conclusions:
- c-myc and max modulate distinct apoptotic pathways.
- The cellular context (presence/absence of growth factors) significantly influences the apoptotic response.
- These findings suggest differential therapeutic strategies targeting c-myc and max pathways in cancer.